EP2632465B1 - Inhibitors of the renal outer medullary potassium channel - Google Patents
Inhibitors of the renal outer medullary potassium channel Download PDFInfo
- Publication number
- EP2632465B1 EP2632465B1 EP11836899.2A EP11836899A EP2632465B1 EP 2632465 B1 EP2632465 B1 EP 2632465B1 EP 11836899 A EP11836899 A EP 11836899A EP 2632465 B1 EP2632465 B1 EP 2632465B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- ethyl
- mmol
- piperazin
- benzonitrile
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 239000003112 inhibitor Substances 0.000 title description 13
- 102000004257 Potassium Channel Human genes 0.000 title description 8
- 108020001213 potassium channel Proteins 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 claims description 172
- 150000003839 salts Chemical class 0.000 claims description 63
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 45
- 125000004122 cyclic group Chemical group 0.000 claims description 24
- 229910052799 carbon Inorganic materials 0.000 claims description 18
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 17
- 238000011282 treatment Methods 0.000 claims description 16
- 206010020772 Hypertension Diseases 0.000 claims description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 11
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 239000013543 active substance Substances 0.000 claims description 10
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 8
- 208000035475 disorder Diseases 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 206010019280 Heart failures Diseases 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 229910052727 yttrium Inorganic materials 0.000 claims description 5
- GKZBQPSXHBJOPU-UHFFFAOYSA-N 1,4-bis[2-(4-nitrophenyl)ethyl]piperazine Chemical compound C1=CC([N+](=O)[O-])=CC=C1CCN1CCN(CCC=2C=CC(=CC=2)[N+]([O-])=O)CC1 GKZBQPSXHBJOPU-UHFFFAOYSA-N 0.000 claims description 4
- ARMYQKGAFQAFJP-UHFFFAOYSA-N 2-methoxy-4-[2-[4-[2-(1-oxo-3h-2-benzofuran-5-yl)ethyl]-2-(trifluoromethyl)piperazin-1-yl]ethyl]benzonitrile Chemical compound C1=C(C#N)C(OC)=CC(CCN2C(CN(CCC=3C=C4COC(=O)C4=CC=3)CC2)C(F)(F)F)=C1 ARMYQKGAFQAFJP-UHFFFAOYSA-N 0.000 claims description 4
- 230000001154 acute effect Effects 0.000 claims description 4
- 206010012601 diabetes mellitus Diseases 0.000 claims description 4
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- 238000011321 prophylaxis Methods 0.000 claims description 4
- 238000002560 therapeutic procedure Methods 0.000 claims description 4
- LTPQISPOQQDKAE-HSZRJFAPSA-N (6r)-6-[4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl]-5,6,7,8-tetrahydronaphthalene-2-carbonitrile Chemical compound C1=CC([N+](=O)[O-])=CC=C1CCN1CCN([C@H]2CC3=CC=C(C=C3CC2)C#N)CC1 LTPQISPOQQDKAE-HSZRJFAPSA-N 0.000 claims description 3
- AMKWVRGTVQDBBV-UHFFFAOYSA-N 2-(methylamino)-4-[2-[4-[2-(1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile Chemical compound C1=C(C#N)C(NC)=CC(CCN2CCN(CCC=3C=C4COC(=O)C4=CC=3)CC2)=C1 AMKWVRGTVQDBBV-UHFFFAOYSA-N 0.000 claims description 3
- WNZQDUSMALZDQF-UHFFFAOYSA-N 2-benzofuran-1(3H)-one Chemical compound C1=CC=C2C(=O)OCC2=C1 WNZQDUSMALZDQF-UHFFFAOYSA-N 0.000 claims description 3
- YTNSJONVJGMWDS-UHFFFAOYSA-N 2-methoxy-4-[2-[4-[2-(1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile Chemical compound C1=C(C#N)C(OC)=CC(CCN2CCN(CCC=3C=C4COC(=O)C4=CC=3)CC2)=C1 YTNSJONVJGMWDS-UHFFFAOYSA-N 0.000 claims description 3
- ZAMWSSZOIWRTBM-UHFFFAOYSA-N 2-methoxy-4-[2-[4-[2-(3-methyl-1-oxo-3,4-dihydroisochromen-6-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile Chemical compound C1=C(C#N)C(OC)=CC(CCN2CCN(CCC=3C=C4CC(C)OC(=O)C4=CC=3)CC2)=C1 ZAMWSSZOIWRTBM-UHFFFAOYSA-N 0.000 claims description 3
- DVFVDIAPTAUANY-UHFFFAOYSA-N 2-methoxy-4-[2-[4-[2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile Chemical compound C1=C(C#N)C(OC)=CC(CCN2CCN(CCC=3C(=C4COC(=O)C4=CC=3)C)CC2)=C1 DVFVDIAPTAUANY-UHFFFAOYSA-N 0.000 claims description 3
- ITKLWGVJMIJZNQ-UHFFFAOYSA-N 4-[2-[4-[2-(1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile Chemical compound C=1C=C2C(=O)OCC2=CC=1CCN(CC1)CCN1CCC1=CC=C(C#N)C=C1 ITKLWGVJMIJZNQ-UHFFFAOYSA-N 0.000 claims description 3
- UMQXZSKUBTWYIX-UHFFFAOYSA-N 4-[2-[4-[2-(4-cyanophenyl)ethyl]piperazin-1-yl]ethyl]benzonitrile Chemical compound C1=CC(C#N)=CC=C1CCN1CCN(CCC=2C=CC(=CC=2)C#N)CC1 UMQXZSKUBTWYIX-UHFFFAOYSA-N 0.000 claims description 3
- ZNTNKDXCYWIVKT-UHFFFAOYSA-N 4-fluoro-2-methoxy-3-[2-[4-[2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile Chemical compound FC1=CC=C(C#N)C(OC)=C1CCN1CCN(CCC=2C(=C3COC(=O)C3=CC=2)C)CC1 ZNTNKDXCYWIVKT-UHFFFAOYSA-N 0.000 claims description 3
- OHSQWDHNRKNTRQ-UHFFFAOYSA-N 4-methyl-5-[2-[4-[2-[6-(tetrazol-1-yl)pyridin-3-yl]ethyl]piperazin-1-yl]ethyl]-3h-2-benzofuran-1-one Chemical compound CC1=C2COC(=O)C2=CC=C1CCN(CC1)CCN1CCC(C=N1)=CC=C1N1C=NN=N1 OHSQWDHNRKNTRQ-UHFFFAOYSA-N 0.000 claims description 3
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 3
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 208000010125 myocardial infarction Diseases 0.000 claims description 3
- 230000012495 positive regulation of renal sodium excretion Effects 0.000 claims description 3
- 229910052702 rhenium Inorganic materials 0.000 claims description 3
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 3
- CHZRGUYJHIAPNU-SFTDATJTSA-N (1s,4s)-2,5-bis[2-(4-nitrophenyl)ethyl]-2,5-diazabicyclo[2.2.1]heptane Chemical compound C([C@]1(N(C[C@]2([H])C1)CCC=1C=CC(=CC=1)[N+]([O-])=O)[H])N2CCC1=CC=C([N+]([O-])=O)C=C1 CHZRGUYJHIAPNU-SFTDATJTSA-N 0.000 claims description 2
- MKKDFNSMCLDIPP-PMACEKPBSA-N (3s)-3-methyl-6-[2-[4-[2-[(3s)-3-methyl-1-oxo-3,4-dihydroisochromen-6-yl]ethyl]piperazin-1-yl]ethyl]-3,4-dihydroisochromen-1-one Chemical compound O=C1O[C@@H](C)CC2=CC(CCN3CCN(CC3)CCC=3C=C4C[C@@H](OC(=O)C4=CC=3)C)=CC=C21 MKKDFNSMCLDIPP-PMACEKPBSA-N 0.000 claims description 2
- JHSMZABRVHYQKB-UHFFFAOYSA-N 2,2-dimethyl-1,4-bis[2-(4-nitrophenyl)ethyl]piperazine Chemical compound C1CN(CCC=2C=CC(=CC=2)[N+]([O-])=O)C(C)(C)CN1CCC1=CC=C([N+]([O-])=O)C=C1 JHSMZABRVHYQKB-UHFFFAOYSA-N 0.000 claims description 2
- YVHUVIOZANOSIW-UHFFFAOYSA-N 2-cyclopropyloxy-4-[2-[4-[2-(1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile Chemical compound C=1C=C2C(=O)OCC2=CC=1CCN(CC1)CCN1CCC(C=1)=CC=C(C#N)C=1OC1CC1 YVHUVIOZANOSIW-UHFFFAOYSA-N 0.000 claims description 2
- UIGDPUDQDMXRLV-UHFFFAOYSA-N 2-ethoxy-4-[2-[4-[2-(1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile Chemical compound C1=C(C#N)C(OCC)=CC(CCN2CCN(CCC=3C=C4COC(=O)C4=CC=3)CC2)=C1 UIGDPUDQDMXRLV-UHFFFAOYSA-N 0.000 claims description 2
- XPHJICKYBJRKLW-UHFFFAOYSA-N 2-fluoro-4-[2-[4-[2-(1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile Chemical compound C1=C(C#N)C(F)=CC(CCN2CCN(CCC=3C=C4COC(=O)C4=CC=3)CC2)=C1 XPHJICKYBJRKLW-UHFFFAOYSA-N 0.000 claims description 2
- GMOVOAFQRUKOBK-UHFFFAOYSA-N 3-chloro-2-fluoro-4-[2-[4-[2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile Chemical compound CC1=C2COC(=O)C2=CC=C1CCN(CC1)CCN1CCC1=CC=C(C#N)C(F)=C1Cl GMOVOAFQRUKOBK-UHFFFAOYSA-N 0.000 claims description 2
- WYTKSIBAYTWHIA-UHFFFAOYSA-N 4-[2-[4-[2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]naphthalene-1-carbonitrile Chemical compound C1=CC=C2C(CCN3CCN(CC3)CCC3=CC=C4C(=O)OCC4=C3C)=CC=C(C#N)C2=C1 WYTKSIBAYTWHIA-UHFFFAOYSA-N 0.000 claims description 2
- AXDIAIUDISGHEP-UHFFFAOYSA-N 4-fluoro-2-methoxy-3-[2-[4-[2-(1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile Chemical compound FC1=CC=C(C#N)C(OC)=C1CCN1CCN(CCC=2C=C3COC(=O)C3=CC=2)CC1 AXDIAIUDISGHEP-UHFFFAOYSA-N 0.000 claims description 2
- 208000009304 Acute Kidney Injury Diseases 0.000 claims description 2
- 206010002383 Angina Pectoris Diseases 0.000 claims description 2
- 201000001320 Atherosclerosis Diseases 0.000 claims description 2
- 206010048962 Brain oedema Diseases 0.000 claims description 2
- 208000024940 Dent disease Diseases 0.000 claims description 2
- 206010052337 Diastolic dysfunction Diseases 0.000 claims description 2
- 206010048554 Endothelial dysfunction Diseases 0.000 claims description 2
- 208000037147 Hypercalcaemia Diseases 0.000 claims description 2
- 206010020852 Hypertonia Diseases 0.000 claims description 2
- 208000027530 Meniere disease Diseases 0.000 claims description 2
- 206010029164 Nephrotic syndrome Diseases 0.000 claims description 2
- 208000007718 Stable Angina Diseases 0.000 claims description 2
- 208000006011 Stroke Diseases 0.000 claims description 2
- 208000007536 Thrombosis Diseases 0.000 claims description 2
- 208000007814 Unstable Angina Diseases 0.000 claims description 2
- 208000006752 brain edema Diseases 0.000 claims description 2
- 208000020832 chronic kidney disease Diseases 0.000 claims description 2
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 2
- 230000008694 endothelial dysfunction Effects 0.000 claims description 2
- 230000000148 hypercalcaemia Effects 0.000 claims description 2
- 208000030915 hypercalcemia disease Diseases 0.000 claims description 2
- 208000017169 kidney disease Diseases 0.000 claims description 2
- 201000011461 pre-eclampsia Diseases 0.000 claims description 2
- 230000002685 pulmonary effect Effects 0.000 claims description 2
- 229910052705 radium Inorganic materials 0.000 claims description 2
- 208000037803 restenosis Diseases 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- QMYVYLTULYDWDF-UHFFFAOYSA-N 4-methyl-5-[2-[4-[2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]-3h-2-benzofuran-1-one Chemical compound C1=C2C(=O)OCC2=C(C)C(CCN2CCN(CC2)CCC2=CC=C3C(=O)OCC3=C2C)=C1 QMYVYLTULYDWDF-UHFFFAOYSA-N 0.000 claims 2
- VXYCOZOZNNSDOG-UHFFFAOYSA-N 4-methyl-5-[2-[4-[2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)propyl]piperazin-1-yl]ethyl]-3h-2-benzofuran-1-one Chemical compound C1=C2C(=O)OCC2=C(C)C(C(CN2CCN(CCC=3C(=C4COC(=O)C4=CC=3)C)CC2)C)=C1 VXYCOZOZNNSDOG-UHFFFAOYSA-N 0.000 claims 2
- DIHYTTBUZGDONK-UHFFFAOYSA-N C(C)OC1=C(C#N)C=CC(=C1)CCN1CCN(CC1)CCC1=CC2=C(C(OC2)=O)C=C1.C1(OCC2=C1C=CC=C2)=O Chemical compound C(C)OC1=C(C#N)C=CC(=C1)CCN1CCN(CC1)CCC1=CC2=C(C(OC2)=O)C=C1.C1(OCC2=C1C=CC=C2)=O DIHYTTBUZGDONK-UHFFFAOYSA-N 0.000 claims 1
- 208000000913 Kidney Calculi Diseases 0.000 claims 1
- 206010029148 Nephrolithiasis Diseases 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 450
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 441
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 277
- 239000000203 mixture Substances 0.000 description 240
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 222
- 239000000243 solution Substances 0.000 description 191
- 238000006243 chemical reaction Methods 0.000 description 181
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 174
- 235000019439 ethyl acetate Nutrition 0.000 description 168
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 164
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 163
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 159
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 155
- 239000000047 product Substances 0.000 description 135
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 118
- 239000012267 brine Substances 0.000 description 114
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 114
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 104
- 238000005160 1H NMR spectroscopy Methods 0.000 description 98
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 97
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 94
- 229910052938 sodium sulfate Inorganic materials 0.000 description 90
- 239000012044 organic layer Substances 0.000 description 79
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 75
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 75
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 72
- 230000015572 biosynthetic process Effects 0.000 description 71
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 60
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 60
- 238000003756 stirring Methods 0.000 description 60
- 229910052757 nitrogen Inorganic materials 0.000 description 59
- 239000000543 intermediate Substances 0.000 description 57
- 235000011152 sodium sulphate Nutrition 0.000 description 56
- 239000011541 reaction mixture Substances 0.000 description 53
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 52
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 50
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 47
- -1 alkali metal salts Chemical class 0.000 description 44
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 44
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 44
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 42
- 238000004811 liquid chromatography Methods 0.000 description 40
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
- 239000002904 solvent Substances 0.000 description 39
- 238000004809 thin layer chromatography Methods 0.000 description 39
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 38
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 37
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 37
- 239000007787 solid Substances 0.000 description 37
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 36
- 238000003818 flash chromatography Methods 0.000 description 36
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 36
- 238000004128 high performance liquid chromatography Methods 0.000 description 35
- 239000007832 Na2SO4 Substances 0.000 description 34
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 34
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 34
- 239000012074 organic phase Substances 0.000 description 33
- 239000003921 oil Substances 0.000 description 32
- 235000019198 oils Nutrition 0.000 description 32
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 31
- 238000000746 purification Methods 0.000 description 31
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 30
- 239000010410 layer Substances 0.000 description 29
- 238000000034 method Methods 0.000 description 28
- 230000002829 reductive effect Effects 0.000 description 27
- 150000001299 aldehydes Chemical class 0.000 description 26
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 24
- UKFTXWKNVSVVCJ-UHFFFAOYSA-N 2-[(6-hydrazinylpyridazin-3-yl)-(2-hydroxyethyl)amino]ethanol;hydron;dichloride Chemical class Cl.Cl.NNC1=CC=C(N(CCO)CCO)N=N1 UKFTXWKNVSVVCJ-UHFFFAOYSA-N 0.000 description 23
- 239000000725 suspension Substances 0.000 description 23
- 239000000741 silica gel Substances 0.000 description 22
- 229910002027 silica gel Inorganic materials 0.000 description 22
- 238000003556 assay Methods 0.000 description 21
- VJUJYWABYDPKLP-UHFFFAOYSA-N 4-methyl-5-(2-piperazin-1-ylethyl)-3h-2-benzofuran-1-one;hydrochloride Chemical compound Cl.CC1=C2COC(=O)C2=CC=C1CCN1CCNCC1 VJUJYWABYDPKLP-UHFFFAOYSA-N 0.000 description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
- 238000003786 synthesis reaction Methods 0.000 description 20
- NTURQZFFJDCTMZ-UHFFFAOYSA-N 1-(2-bromoethyl)-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(CCBr)C=C1 NTURQZFFJDCTMZ-UHFFFAOYSA-N 0.000 description 19
- IZUUEFUOYINQJH-UHFFFAOYSA-N 5-(2-piperazin-1-ylethyl)-3h-2-benzofuran-1-one;hydrochloride Chemical compound Cl.C=1C=C2C(=O)OCC2=CC=1CCN1CCNCC1 IZUUEFUOYINQJH-UHFFFAOYSA-N 0.000 description 19
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 19
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 19
- 229910000029 sodium carbonate Inorganic materials 0.000 description 19
- 239000007858 starting material Substances 0.000 description 19
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 18
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 17
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 17
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 17
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 16
- 238000010898 silica gel chromatography Methods 0.000 description 16
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 16
- 239000003039 volatile agent Substances 0.000 description 16
- 229910000027 potassium carbonate Inorganic materials 0.000 description 15
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 15
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 14
- IGLNJRXAVVLDKE-OUBTZVSYSA-N Rubidium-86 Chemical compound [86Rb] IGLNJRXAVVLDKE-OUBTZVSYSA-N 0.000 description 14
- 125000001309 chloro group Chemical group Cl* 0.000 description 14
- YLGRTLMDMVAFNI-UHFFFAOYSA-N tributyl(prop-2-enyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)CC=C YLGRTLMDMVAFNI-UHFFFAOYSA-N 0.000 description 14
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 13
- AMIQLDROUFGBPI-UHFFFAOYSA-N 2-methoxy-4-(2-oxoethyl)benzonitrile Chemical compound COC1=CC(CC=O)=CC=C1C#N AMIQLDROUFGBPI-UHFFFAOYSA-N 0.000 description 12
- 239000003814 drug Substances 0.000 description 12
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 12
- 108091006146 Channels Proteins 0.000 description 11
- 125000004093 cyano group Chemical group *C#N 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 11
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 11
- 238000006268 reductive amination reaction Methods 0.000 description 11
- 238000010992 reflux Methods 0.000 description 11
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 10
- 235000011054 acetic acid Nutrition 0.000 description 10
- 229960000583 acetic acid Drugs 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
- 239000012043 crude product Substances 0.000 description 10
- 235000017557 sodium bicarbonate Nutrition 0.000 description 10
- 238000000638 solvent extraction Methods 0.000 description 10
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 10
- ILBOKWNLAXHFBK-UHFFFAOYSA-N 2-(1-oxo-3h-2-benzofuran-5-yl)acetaldehyde Chemical compound O=CCC1=CC=C2C(=O)OCC2=C1 ILBOKWNLAXHFBK-UHFFFAOYSA-N 0.000 description 9
- MOVXCAASKHUXNS-UHFFFAOYSA-N 5-(2-piperazin-1-ylethyl)-3h-2-benzofuran-1-one Chemical compound C=1C=C2C(=O)OCC2=CC=1CCN1CCNCC1 MOVXCAASKHUXNS-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 239000012448 Lithium borohydride Substances 0.000 description 9
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 239000012230 colorless oil Substances 0.000 description 9
- 239000002934 diuretic Substances 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 235000019341 magnesium sulphate Nutrition 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 9
- XYQYKGMYGDVLPX-UHFFFAOYSA-N 1-[2-(4-nitrophenyl)ethyl]piperazine;hydrochloride Chemical compound Cl.C1=CC([N+](=O)[O-])=CC=C1CCN1CCNCC1 XYQYKGMYGDVLPX-UHFFFAOYSA-N 0.000 description 8
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 239000011780 sodium chloride Substances 0.000 description 8
- 235000019345 sodium thiosulphate Nutrition 0.000 description 8
- JEUFBPQAVLSWLV-UHFFFAOYSA-N 2-fluoro-4-(2-oxoethyl)benzonitrile Chemical compound FC1=CC(CC=O)=CC=C1C#N JEUFBPQAVLSWLV-UHFFFAOYSA-N 0.000 description 7
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 7
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- 239000012131 assay buffer Substances 0.000 description 7
- 125000001246 bromo group Chemical group Br* 0.000 description 7
- 238000004587 chromatography analysis Methods 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 239000012458 free base Substances 0.000 description 7
- 229910052708 sodium Inorganic materials 0.000 description 7
- 229910000104 sodium hydride Inorganic materials 0.000 description 7
- 159000000000 sodium salts Chemical class 0.000 description 7
- 239000003643 water by type Substances 0.000 description 7
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 7
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 description 6
- ONEWFGBXKNUPHD-UHFFFAOYSA-N 2-fluoro-4-prop-2-enylbenzonitrile Chemical compound FC1=CC(CC=C)=CC=C1C#N ONEWFGBXKNUPHD-UHFFFAOYSA-N 0.000 description 6
- ZAUYVJAYCHMTHJ-UHFFFAOYSA-N 5-(2-bromoethyl)-3h-2-benzofuran-1-one Chemical compound BrCCC1=CC=C2C(=O)OCC2=C1 ZAUYVJAYCHMTHJ-UHFFFAOYSA-N 0.000 description 6
- JQFKKMDALIEUSV-UHFFFAOYSA-N 5-fluoro-2-methoxy-4-(2-oxoethyl)benzonitrile Chemical compound COC1=CC(CC=O)=C(F)C=C1C#N JQFKKMDALIEUSV-UHFFFAOYSA-N 0.000 description 6
- STHOMBUIKADCFV-UHFFFAOYSA-N 5-prop-2-enyl-3h-2-benzofuran-1-one Chemical compound C=CCC1=CC=C2C(=O)OCC2=C1 STHOMBUIKADCFV-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- 239000004593 Epoxy Substances 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 238000004007 reversed phase HPLC Methods 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 6
- 239000012453 solvate Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 5
- XVVFOMUUYARANW-UHFFFAOYSA-N 2-methoxy-4-(2-oxopropyl)benzonitrile Chemical compound COC1=CC(CC(C)=O)=CC=C1C#N XVVFOMUUYARANW-UHFFFAOYSA-N 0.000 description 5
- XVEJOWYOVVGMDN-UHFFFAOYSA-N 4-methyl-5-prop-2-enyl-3h-2-benzofuran-1-one Chemical compound C1=C(CC=C)C(C)=C2COC(=O)C2=C1 XVEJOWYOVVGMDN-UHFFFAOYSA-N 0.000 description 5
- LZCNFBITEYOXLV-UHFFFAOYSA-N 5-prop-2-enyl-2,1,3-benzoxadiazole Chemical compound C1=C(CC=C)C=CC2=NON=C21 LZCNFBITEYOXLV-UHFFFAOYSA-N 0.000 description 5
- AKMQFDBAVMKKQC-UHFFFAOYSA-N 6-(1,3-dioxolan-2-ylmethyl)-3-methyl-3,4-dihydroisochromen-1-one Chemical compound C=1C=C2C(=O)OC(C)CC2=CC=1CC1OCCO1 AKMQFDBAVMKKQC-UHFFFAOYSA-N 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 5
- 229910004373 HOAc Inorganic materials 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 description 5
- 230000008901 benefit Effects 0.000 description 5
- 239000006227 byproduct Substances 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 230000001882 diuretic effect Effects 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000002480 mineral oil Substances 0.000 description 5
- 235000010446 mineral oil Nutrition 0.000 description 5
- 230000002265 prevention Effects 0.000 description 5
- 229940002612 prodrug Drugs 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- 150000003384 small molecules Chemical class 0.000 description 5
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- RRIPHUBKNVVTBM-UHFFFAOYSA-N tert-butyl n,n-bis(prop-2-enyl)carbamate Chemical compound CC(C)(C)OC(=O)N(CC=C)CC=C RRIPHUBKNVVTBM-UHFFFAOYSA-N 0.000 description 5
- AKMQFDBAVMKKQC-VIFPVBQESA-N (3s)-6-(1,3-dioxolan-2-ylmethyl)-3-methyl-3,4-dihydroisochromen-1-one Chemical compound C([C@@H](OC(=O)C1=CC=2)C)C1=CC=2CC1OCCO1 AKMQFDBAVMKKQC-VIFPVBQESA-N 0.000 description 4
- RJOUZCZUQPOORI-HNNXBMFYSA-N (6s)-6-piperazin-1-yl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile Chemical compound N1([C@@H]2CC3=CC=C(C=C3CC2)C#N)CCNCC1 RJOUZCZUQPOORI-HNNXBMFYSA-N 0.000 description 4
- GGFOQOWFRMNKMJ-UHFFFAOYSA-N 2-[6-(tetrazol-1-yl)pyridin-3-yl]acetaldehyde Chemical compound N1=CC(CC=O)=CC=C1N1N=NN=C1 GGFOQOWFRMNKMJ-UHFFFAOYSA-N 0.000 description 4
- JPMASVDFLRVTEG-UHFFFAOYSA-N 2-chloro-4-(2-oxoethyl)benzonitrile Chemical compound ClC1=CC(CC=O)=CC=C1C#N JPMASVDFLRVTEG-UHFFFAOYSA-N 0.000 description 4
- WIVLTMABLIYLJQ-UHFFFAOYSA-N 2-ethoxy-4-(2-oxoethyl)benzonitrile Chemical compound CCOC1=CC(CC=O)=CC=C1C#N WIVLTMABLIYLJQ-UHFFFAOYSA-N 0.000 description 4
- HJJHYBZKVAXCCR-UHFFFAOYSA-N 2-methoxy-3-methyl-4-(2-oxoethyl)benzonitrile Chemical compound COC1=C(C)C(CC=O)=CC=C1C#N HJJHYBZKVAXCCR-UHFFFAOYSA-N 0.000 description 4
- QGUSDJLRQXNUKB-UHFFFAOYSA-N 3-fluoro-2-methoxy-4-(2-oxoethyl)benzonitrile Chemical compound COC1=C(F)C(CC=O)=CC=C1C#N QGUSDJLRQXNUKB-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- PAHSHGVACWNGEY-UHFFFAOYSA-N 4-bromo-2-hydroxybenzonitrile Chemical compound OC1=CC(Br)=CC=C1C#N PAHSHGVACWNGEY-UHFFFAOYSA-N 0.000 description 4
- BSGZLDWGDBBFHH-UHFFFAOYSA-N 4-formyl-3,4-dihydro-2h-chromene-7-carbonitrile Chemical compound N#CC1=CC=C2C(C=O)CCOC2=C1 BSGZLDWGDBBFHH-UHFFFAOYSA-N 0.000 description 4
- DSTOPNDVXROHLG-UHFFFAOYSA-N 4-methyl-5-(1-piperazin-1-ylpropan-2-yl)-3h-2-benzofuran-1-one Chemical compound C=1C=C2C(=O)OCC2=C(C)C=1C(C)CN1CCNCC1 DSTOPNDVXROHLG-UHFFFAOYSA-N 0.000 description 4
- IRAKZLQFUGTIGE-UHFFFAOYSA-N 5-bromo-4-methyl-3h-2-benzofuran-1-one Chemical compound C1=C(Br)C(C)=C2COC(=O)C2=C1 IRAKZLQFUGTIGE-UHFFFAOYSA-N 0.000 description 4
- RJOUZCZUQPOORI-UHFFFAOYSA-N 6-piperazin-1-yl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile Chemical compound C1CC2=CC(C#N)=CC=C2CC1N1CCNCC1 RJOUZCZUQPOORI-UHFFFAOYSA-N 0.000 description 4
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- 239000007983 Tris buffer Substances 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 230000029936 alkylation Effects 0.000 description 4
- 238000005804 alkylation reaction Methods 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 229940030606 diuretics Drugs 0.000 description 4
- 235000003599 food sweetener Nutrition 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 230000036515 potency Effects 0.000 description 4
- 238000012746 preparative thin layer chromatography Methods 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- 239000012047 saturated solution Substances 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000003765 sweetening agent Substances 0.000 description 4
- KQRQBVURQOSBJG-UHFFFAOYSA-N tert-butyl 4-(6-cyano-1,2,3,4-tetrahydronaphthalen-2-yl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1CC2=CC=C(C#N)C=C2CC1 KQRQBVURQOSBJG-UHFFFAOYSA-N 0.000 description 4
- 229910052716 thallium Inorganic materials 0.000 description 4
- BKVIYDNLLOSFOA-UHFFFAOYSA-N thallium Chemical compound [Tl] BKVIYDNLLOSFOA-UHFFFAOYSA-N 0.000 description 4
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 4
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 4
- ONDSBJMLAHVLMI-UHFFFAOYSA-N trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- FAPDYEQZMWCIDB-CSKARUKUSA-N (1e)-1-(methoxymethylidene)-2,3-dihydroindene-4-carbonitrile Chemical compound C1=CC=C(C#N)C2=C1C(=C/OC)/CC2 FAPDYEQZMWCIDB-CSKARUKUSA-N 0.000 description 3
- XYDXDWXAAQXHLK-UHFFFAOYSA-N (3-bromo-2-methylphenyl)methanol Chemical compound CC1=C(Br)C=CC=C1CO XYDXDWXAAQXHLK-UHFFFAOYSA-N 0.000 description 3
- PONGXMDLEGURRQ-NSHDSACASA-N (6s)-6-amino-5,6,7,8-tetrahydronaphthalene-2-carbonitrile Chemical compound N#CC1=CC=C2C[C@@H](N)CCC2=C1 PONGXMDLEGURRQ-NSHDSACASA-N 0.000 description 3
- QRXNZDWNYKKABJ-UHFFFAOYSA-N 1,4-bis[2-(4-bromophenyl)ethyl]piperazine Chemical compound C1=CC(Br)=CC=C1CCN1CCN(CCC=2C=CC(Br)=CC=2)CC1 QRXNZDWNYKKABJ-UHFFFAOYSA-N 0.000 description 3
- REPABDBBFKKXLP-UHFFFAOYSA-N 1-(piperazin-1-ylmethyl)-2,3-dihydro-1h-indene-4-carbonitrile Chemical compound C1CC=2C(C#N)=CC=CC=2C1CN1CCNCC1 REPABDBBFKKXLP-UHFFFAOYSA-N 0.000 description 3
- LUDMGGRIBMKBPF-UHFFFAOYSA-N 1-[2-(6-nitropyridin-3-yl)ethyl]piperazine;hydrochloride Chemical compound Cl.C1=NC([N+](=O)[O-])=CC=C1CCN1CCNCC1 LUDMGGRIBMKBPF-UHFFFAOYSA-N 0.000 description 3
- SCTBWJINDJVNDM-UHFFFAOYSA-N 1-oxo-2,3-dihydroindene-4-carbonitrile Chemical compound C1=CC=C(C#N)C2=C1C(=O)CC2 SCTBWJINDJVNDM-UHFFFAOYSA-N 0.000 description 3
- ZMOCVTPLPAWDSA-UHFFFAOYSA-N 2,3,5-trifluoro-4-(2-oxoethyl)benzonitrile Chemical compound FC1=CC(C#N)=C(F)C(F)=C1CC=O ZMOCVTPLPAWDSA-UHFFFAOYSA-N 0.000 description 3
- GDTBACYBTXRQMO-UHFFFAOYSA-N 2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)acetic acid Chemical compound C1=C(CC(O)=O)C(C)=C2COC(=O)C2=C1 GDTBACYBTXRQMO-UHFFFAOYSA-N 0.000 description 3
- AHDVGTFQMRQEST-UHFFFAOYSA-N 2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)propanal Chemical compound O=CC(C)C1=CC=C2C(=O)OCC2=C1C AHDVGTFQMRQEST-UHFFFAOYSA-N 0.000 description 3
- KTYKMXXSYPUDNW-UHFFFAOYSA-N 2-(4-nitrophenyl)-1-[4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl]propan-1-one Chemical compound C=1C=C([N+]([O-])=O)C=CC=1C(C)C(=O)N(CC1)CCN1CCC1=CC=C([N+]([O-])=O)C=C1 KTYKMXXSYPUDNW-UHFFFAOYSA-N 0.000 description 3
- NBFUEAKPOVIYPN-UHFFFAOYSA-N 2-(methylamino)-4-(2-piperazin-1-ylethyl)benzonitrile Chemical compound C1=C(C#N)C(NC)=CC(CCN2CCNCC2)=C1 NBFUEAKPOVIYPN-UHFFFAOYSA-N 0.000 description 3
- KWTMJJGYSVVGFP-UHFFFAOYSA-N 2-[3-(1,3-dioxoisoindol-2-yl)phenyl]acetic acid Chemical compound OC(=O)CC1=CC=CC(N2C(C3=CC=CC=C3C2=O)=O)=C1 KWTMJJGYSVVGFP-UHFFFAOYSA-N 0.000 description 3
- LCEFXLWEIXRZNU-UHFFFAOYSA-N 2-methoxy-4-(1-oxopropan-2-yl)benzonitrile Chemical compound COC1=CC(C(C)C=O)=CC=C1C#N LCEFXLWEIXRZNU-UHFFFAOYSA-N 0.000 description 3
- WHISKDGFPYYLEA-UHFFFAOYSA-N 2-methoxy-4-(2-methyl-1-oxopropan-2-yl)benzonitrile Chemical compound COC1=CC(C(C)(C)C=O)=CC=C1C#N WHISKDGFPYYLEA-UHFFFAOYSA-N 0.000 description 3
- UDUNAFIGUIQMJZ-UHFFFAOYSA-N 2-methoxy-4-prop-2-enylbenzonitrile Chemical compound COC1=CC(CC=C)=CC=C1C#N UDUNAFIGUIQMJZ-UHFFFAOYSA-N 0.000 description 3
- ODKBNLABFQTMHV-UHFFFAOYSA-N 2-piperazin-1-yl-2,3-dihydro-1h-indene-5-carbonitrile;hydrochloride Chemical compound Cl.C1C2=CC(C#N)=CC=C2CC1N1CCNCC1 ODKBNLABFQTMHV-UHFFFAOYSA-N 0.000 description 3
- PXCWHUJHPMMJLF-UHFFFAOYSA-N 2-tert-butyl-4-[2-(1-oxo-3H-2-benzofuran-5-yl)ethyl]piperazine-1-carboxylic acid Chemical compound C1CN(C(O)=O)C(C(C)(C)C)CN1CCC1=CC=C(C(=O)OC2)C2=C1 PXCWHUJHPMMJLF-UHFFFAOYSA-N 0.000 description 3
- PPTKXQMDVMZGQK-UHFFFAOYSA-N 3-chloro-2-fluoro-4-(2-oxoethyl)benzonitrile Chemical compound FC1=C(Cl)C(CC=O)=CC=C1C#N PPTKXQMDVMZGQK-UHFFFAOYSA-N 0.000 description 3
- DNADYNZKFMAYSO-UHFFFAOYSA-N 3-chloro-2-methoxy-4-(2-oxoethyl)benzonitrile Chemical compound COC1=C(Cl)C(CC=O)=CC=C1C#N DNADYNZKFMAYSO-UHFFFAOYSA-N 0.000 description 3
- GTGURPVLQUHXGE-UHFFFAOYSA-N 4-(1-hydroxy-2-methylpropan-2-yl)-2-methoxybenzonitrile Chemical compound COC1=CC(C(C)(C)CO)=CC=C1C#N GTGURPVLQUHXGE-UHFFFAOYSA-N 0.000 description 3
- GJDMNDWRZGEUGT-UHFFFAOYSA-N 4-(2,3-dihydroxypropyl)-2,6-difluorobenzonitrile Chemical compound OCC(O)CC1=CC(F)=C(C#N)C(F)=C1 GJDMNDWRZGEUGT-UHFFFAOYSA-N 0.000 description 3
- QTMISMQUUXBAOA-UHFFFAOYSA-N 4-(2,3-dihydroxypropyl)-2-fluorobenzonitrile Chemical compound OCC(O)CC1=CC=C(C#N)C(F)=C1 QTMISMQUUXBAOA-UHFFFAOYSA-N 0.000 description 3
- YDVGMTLHXONPKH-UHFFFAOYSA-N 4-(2,3-dihydroxypropyl)-3-methoxybenzonitrile Chemical compound COC1=CC(C#N)=CC=C1CC(O)CO YDVGMTLHXONPKH-UHFFFAOYSA-N 0.000 description 3
- RQMBXJKQGZOAQX-UHFFFAOYSA-N 4-(2-hydroxypropyl)-2-methoxybenzonitrile Chemical compound COC1=CC(CC(C)O)=CC=C1C#N RQMBXJKQGZOAQX-UHFFFAOYSA-N 0.000 description 3
- AOZBPIAHPQOWMZ-UHFFFAOYSA-N 4-(2-oxoethyl)-2-(trifluoromethoxy)benzonitrile Chemical compound FC(F)(F)OC1=CC(CC=O)=CC=C1C#N AOZBPIAHPQOWMZ-UHFFFAOYSA-N 0.000 description 3
- GXNHPZKHFKNEBB-UHFFFAOYSA-N 4-(2-oxoethyl)naphthalene-1-carbonitrile Chemical compound C1=CC=C2C(CC=O)=CC=C(C#N)C2=C1 GXNHPZKHFKNEBB-UHFFFAOYSA-N 0.000 description 3
- LBXXMNAPNXRKPB-UHFFFAOYSA-N 4-bromo-2-(difluoromethoxy)benzonitrile Chemical compound FC(F)OC1=CC(Br)=CC=C1C#N LBXXMNAPNXRKPB-UHFFFAOYSA-N 0.000 description 3
- CXZJMWSQQASXJB-UHFFFAOYSA-N 4-bromo-2-cyclopropyloxybenzonitrile Chemical compound BrC1=CC=C(C#N)C(OC2CC2)=C1 CXZJMWSQQASXJB-UHFFFAOYSA-N 0.000 description 3
- HGXWRDPQFZKOLZ-UHFFFAOYSA-N 4-bromo-2-fluorobenzonitrile Chemical compound FC1=CC(Br)=CC=C1C#N HGXWRDPQFZKOLZ-UHFFFAOYSA-N 0.000 description 3
- RIKJENUWHKDHIW-UHFFFAOYSA-N 4-formyl-2-methoxybenzonitrile Chemical compound COC1=CC(C=O)=CC=C1C#N RIKJENUWHKDHIW-UHFFFAOYSA-N 0.000 description 3
- XMNVHPRNQXBJDI-UHFFFAOYSA-N 4-formyl-2-methylbenzonitrile Chemical compound CC1=CC(C=O)=CC=C1C#N XMNVHPRNQXBJDI-UHFFFAOYSA-N 0.000 description 3
- GVWRWNKPXVHRPJ-UHFFFAOYSA-N 4-formyl-3-methylbenzonitrile Chemical compound CC1=CC(C#N)=CC=C1C=O GVWRWNKPXVHRPJ-UHFFFAOYSA-N 0.000 description 3
- HNBATZBPNOJXMX-UHFFFAOYSA-N 4-nitro-1-prop-2-enyl-2-(trifluoromethyl)benzene Chemical compound [O-][N+](=O)C1=CC=C(CC=C)C(C(F)(F)F)=C1 HNBATZBPNOJXMX-UHFFFAOYSA-N 0.000 description 3
- OWEOZKBRNNMRCC-UHFFFAOYSA-N 5-(1,3-dioxolan-2-ylmethyl)-3h-2-benzofuran-1-one Chemical compound C=1C=C2C(=O)OCC2=CC=1CC1OCCO1 OWEOZKBRNNMRCC-UHFFFAOYSA-N 0.000 description 3
- RDESXHSSRWYMNY-UHFFFAOYSA-N 5-(2-hydroxyethyl)-3h-2-benzofuran-1-one Chemical compound OCCC1=CC=C2C(=O)OCC2=C1 RDESXHSSRWYMNY-UHFFFAOYSA-N 0.000 description 3
- FUAJPBCATCQDIV-UHFFFAOYSA-N 5-(2-piperazin-1-ylethyl)-2,1,3-benzoxadiazole Chemical compound C1=CC2=NON=C2C=C1CCN1CCNCC1 FUAJPBCATCQDIV-UHFFFAOYSA-N 0.000 description 3
- RFDJBLWWFYCJHC-UHFFFAOYSA-N 5-[2-[2-(trifluoromethyl)piperazin-1-yl]ethyl]-3h-2-benzofuran-1-one Chemical compound FC(F)(F)C1CNCCN1CCC1=CC=C(C(=O)OC2)C2=C1 RFDJBLWWFYCJHC-UHFFFAOYSA-N 0.000 description 3
- IUSPXLCLQIZFHL-UHFFFAOYSA-N 5-bromo-3h-2-benzofuran-1-one Chemical compound BrC1=CC=C2C(=O)OCC2=C1 IUSPXLCLQIZFHL-UHFFFAOYSA-N 0.000 description 3
- VRIGVEIBZVJEMZ-UHFFFAOYSA-N 5-chloro-2-fluoro-4-(2-oxoethyl)benzonitrile Chemical compound FC1=CC(CC=O)=C(Cl)C=C1C#N VRIGVEIBZVJEMZ-UHFFFAOYSA-N 0.000 description 3
- HIJXRTIKPLHNEC-UHFFFAOYSA-N 5-chloro-2-methoxy-4-(2-oxoethyl)benzonitrile Chemical compound COC1=CC(CC=O)=C(Cl)C=C1C#N HIJXRTIKPLHNEC-UHFFFAOYSA-N 0.000 description 3
- WLVWGQAEAHBBJO-UHFFFAOYSA-N 5-fluoro-4-(2-hydroxyethyl)-2-methoxybenzonitrile Chemical compound COC1=CC(CCO)=C(F)C=C1C#N WLVWGQAEAHBBJO-UHFFFAOYSA-N 0.000 description 3
- IIWBLHFCFKBMTM-UHFFFAOYSA-N 5-formyl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile Chemical compound N#CC1=CC=C2C(C=O)CCCC2=C1 IIWBLHFCFKBMTM-UHFFFAOYSA-N 0.000 description 3
- JWPPMYMAKCDLGA-UHFFFAOYSA-N 6-(tetrazol-1-yl)-3,4-dihydro-1h-naphthalen-2-one Chemical compound C=1C=C2CC(=O)CCC2=CC=1N1C=NN=N1 JWPPMYMAKCDLGA-UHFFFAOYSA-N 0.000 description 3
- FQXNEJZEPHQHEK-UHFFFAOYSA-N 6-bromo-3-methyl-3,4-dihydroisochromen-1-one Chemical compound BrC1=CC=C2C(=O)OC(C)CC2=C1 FQXNEJZEPHQHEK-UHFFFAOYSA-N 0.000 description 3
- MQLXBVVRDDBKAI-UHFFFAOYSA-N 6-fluoro-4-formyl-3,4-dihydro-2h-chromene-7-carbonitrile Chemical compound O=CC1CCOC2=C1C=C(F)C(C#N)=C2 MQLXBVVRDDBKAI-UHFFFAOYSA-N 0.000 description 3
- VFYXRPRIMUJTPO-UHFFFAOYSA-N 6-oxo-7,8-dihydro-5h-naphthalene-2-carbonitrile Chemical compound N#CC1=CC=C2CC(=O)CCC2=C1 VFYXRPRIMUJTPO-UHFFFAOYSA-N 0.000 description 3
- XDOHBWHYRKUUNK-UHFFFAOYSA-N 6-piperazin-1-yl-5,6,7,8-tetrahydrobenzo[f][2,1,3]benzoxadiazole;hydrochloride Chemical compound Cl.C1CNCCN1C1CC2=CC3=NON=C3C=C2CC1 XDOHBWHYRKUUNK-UHFFFAOYSA-N 0.000 description 3
- 239000002083 C09CA01 - Losartan Substances 0.000 description 3
- 206010007559 Cardiac failure congestive Diseases 0.000 description 3
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 208000029422 Hypernatremia Diseases 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
- WEVYAHXRMPXWCK-FIBGUPNXSA-N acetonitrile-d3 Chemical compound [2H]C([2H])([2H])C#N WEVYAHXRMPXWCK-FIBGUPNXSA-N 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000013270 controlled release Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- HJIXMBKGKJJLRU-UHFFFAOYSA-N ditert-butyl 2-(3-bromo-4-cyanophenyl)propanedioate Chemical compound CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)C1=CC=C(C#N)C(Br)=C1 HJIXMBKGKJJLRU-UHFFFAOYSA-N 0.000 description 3
- GREBPDKRBNAIBF-UHFFFAOYSA-N ditert-butyl 2-(4-cyano-2,5-difluorophenyl)propanedioate Chemical compound CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)C1=CC(F)=C(C#N)C=C1F GREBPDKRBNAIBF-UHFFFAOYSA-N 0.000 description 3
- 239000012039 electrophile Substances 0.000 description 3
- PHOIGLOQPXWGOU-UHFFFAOYSA-N ethyl 2-(4-cyano-3-methoxyphenyl)-2-methylpropanoate Chemical compound CCOC(=O)C(C)(C)C1=CC=C(C#N)C(OC)=C1 PHOIGLOQPXWGOU-UHFFFAOYSA-N 0.000 description 3
- JZDQGUMBHPMRHM-UHFFFAOYSA-N ethyl 2-(4-cyano-3-methoxyphenyl)acetate Chemical compound CCOC(=O)CC1=CC=C(C#N)C(OC)=C1 JZDQGUMBHPMRHM-UHFFFAOYSA-N 0.000 description 3
- XQTUHFQPMLEQQI-UHFFFAOYSA-N ethyl 3-(4-cyano-2-methylphenyl)oxirane-2-carboxylate Chemical compound CCOC(=O)C1OC1C1=CC=C(C#N)C=C1C XQTUHFQPMLEQQI-UHFFFAOYSA-N 0.000 description 3
- MHCUCFUYUPGDLQ-UHFFFAOYSA-N ethyl 3-(4-cyano-3-methoxyphenyl)oxirane-2-carboxylate Chemical compound CCOC(=O)C1OC1C1=CC=C(C#N)C(OC)=C1 MHCUCFUYUPGDLQ-UHFFFAOYSA-N 0.000 description 3
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 3
- 230000029142 excretion Effects 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 3
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 3
- 150000004677 hydrates Chemical class 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 230000000155 isotopic effect Effects 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- SJFNDMHZXCUXSA-UHFFFAOYSA-M methoxymethyl(triphenyl)phosphanium;chloride Chemical compound [Cl-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(COC)C1=CC=CC=C1 SJFNDMHZXCUXSA-UHFFFAOYSA-M 0.000 description 3
- CGEDKESQFQUVGG-ZOWNYOTGSA-N methyl (2S)-3-(4-nitrophenyl)-2-piperazin-1-ylpropanoate hydrochloride Chemical compound Cl.C([C@@H](C(=O)OC)N1CCNCC1)C1=CC=C([N+]([O-])=O)C=C1 CGEDKESQFQUVGG-ZOWNYOTGSA-N 0.000 description 3
- AEBLIRXSJFPZCZ-UHFFFAOYSA-N methyl 2-(2-chloro-4-cyano-3-fluorophenyl)acetate Chemical compound COC(=O)CC1=CC=C(C#N)C(F)=C1Cl AEBLIRXSJFPZCZ-UHFFFAOYSA-N 0.000 description 3
- IBLBWBLULPAMNW-UHFFFAOYSA-N methyl 2-(4-cyano-3-fluoro-2-methylphenyl)acetate Chemical compound COC(=O)CC1=CC=C(C#N)C(F)=C1C IBLBWBLULPAMNW-UHFFFAOYSA-N 0.000 description 3
- 239000002833 natriuretic agent Substances 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 229910000489 osmium tetroxide Inorganic materials 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 230000000069 prophylactic effect Effects 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 description 3
- PUCOTNXGFRTWLL-UHFFFAOYSA-N tert-butyl 2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)acetate Chemical compound C1=C(CC(=O)OC(C)(C)C)C(C)=C2COC(=O)C2=C1 PUCOTNXGFRTWLL-UHFFFAOYSA-N 0.000 description 3
- CERRGYXNYPWYAU-UHFFFAOYSA-N tert-butyl 4-[2-(1-oxo-3h-2-benzofuran-5-yl)ethyl]-3-(trifluoromethyl)piperazine-1-carboxylate Chemical compound FC(F)(F)C1CN(C(=O)OC(C)(C)C)CCN1CCC1=CC=C(C(=O)OC2)C2=C1 CERRGYXNYPWYAU-UHFFFAOYSA-N 0.000 description 3
- MAGWKKBFHMIWGU-UHFFFAOYSA-N tert-butyl 4-[2-(3-methyl-1-oxo-3,4-dihydroisochromen-6-yl)ethyl]piperazine-1-carboxylate Chemical compound C=1C=C2C(=O)OC(C)CC2=CC=1CCN1CCN(C(=O)OC(C)(C)C)CC1 MAGWKKBFHMIWGU-UHFFFAOYSA-N 0.000 description 3
- UTBNYOOTSFLRPA-UHFFFAOYSA-N tert-butyl 4-[2-(4-cyano-3-fluorophenyl)ethyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1CCC1=CC=C(C#N)C(F)=C1 UTBNYOOTSFLRPA-UHFFFAOYSA-N 0.000 description 3
- GVMDSPKYLVLAKM-UHFFFAOYSA-N tert-butyl 4-[2-(4-cyano-3-methoxyphenyl)ethyl]-3-(trifluoromethyl)piperazine-1-carboxylate Chemical compound C1=C(C#N)C(OC)=CC(CCN2C(CN(CC2)C(=O)OC(C)(C)C)C(F)(F)F)=C1 GVMDSPKYLVLAKM-UHFFFAOYSA-N 0.000 description 3
- MAGWKKBFHMIWGU-HNNXBMFYSA-N tert-butyl 4-[2-[(3s)-3-methyl-1-oxo-3,4-dihydroisochromen-6-yl]ethyl]piperazine-1-carboxylate Chemical compound C([C@@H](OC(=O)C1=CC=2)C)C1=CC=2CCN1CCN(C(=O)OC(C)(C)C)CC1 MAGWKKBFHMIWGU-HNNXBMFYSA-N 0.000 description 3
- ADIHYKSTHIKMHO-UHFFFAOYSA-N tert-butyl 4-[2-[4-cyano-3-(methylamino)phenyl]ethyl]piperazine-1-carboxylate Chemical compound C1=C(C#N)C(NC)=CC(CCN2CCN(CC2)C(=O)OC(C)(C)C)=C1 ADIHYKSTHIKMHO-UHFFFAOYSA-N 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- 239000011701 zinc Substances 0.000 description 3
- FSTUBPBYFIJRSP-CSKARUKUSA-N (4e)-4-(methoxymethylidene)-2,3-dihydrochromene-7-carbonitrile Chemical compound N#CC1=CC=C2C(=C/OC)/CCOC2=C1 FSTUBPBYFIJRSP-CSKARUKUSA-N 0.000 description 2
- CSFRHBSKLCJZIR-UHFFFAOYSA-N (6-fluoro-4-oxo-2,3-dihydrochromen-7-yl) trifluoromethanesulfonate Chemical compound O=C1CCOC2=C1C=C(F)C(OS(=O)(=O)C(F)(F)F)=C2 CSFRHBSKLCJZIR-UHFFFAOYSA-N 0.000 description 2
- RJOUZCZUQPOORI-OAHLLOKOSA-N (6r)-6-piperazin-1-yl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile Chemical compound N1([C@H]2CC3=CC=C(C=C3CC2)C#N)CCNCC1 RJOUZCZUQPOORI-OAHLLOKOSA-N 0.000 description 2
- LTPQISPOQQDKAE-QHCPKHFHSA-N (6s)-6-[4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl]-5,6,7,8-tetrahydronaphthalene-2-carbonitrile Chemical compound C1=CC([N+](=O)[O-])=CC=C1CCN1CCN([C@@H]2CC3=CC=C(C=C3CC2)C#N)CC1 LTPQISPOQQDKAE-QHCPKHFHSA-N 0.000 description 2
- HYGRXCVLCFMFTF-UHFFFAOYSA-N 1,4-bis[1-(4-nitrophenyl)propan-2-yl]piperazine Chemical compound C1CN(C(C)CC=2C=CC(=CC=2)[N+]([O-])=O)CCN1C(C)CC1=CC=C([N+]([O-])=O)C=C1 HYGRXCVLCFMFTF-UHFFFAOYSA-N 0.000 description 2
- GEWWCWZGHNIUBW-UHFFFAOYSA-N 1-(4-nitrophenyl)propan-2-one Chemical compound CC(=O)CC1=CC=C([N+]([O-])=O)C=C1 GEWWCWZGHNIUBW-UHFFFAOYSA-N 0.000 description 2
- KXJZJIVYKFXQMP-UHFFFAOYSA-N 1-(5-nitro-2,3-dihydro-1h-inden-2-yl)piperazine Chemical compound C1C2=CC([N+](=O)[O-])=CC=C2CC1N1CCNCC1 KXJZJIVYKFXQMP-UHFFFAOYSA-N 0.000 description 2
- HATMFSKQAITDIR-UHFFFAOYSA-N 1-[2-(4-bromophenyl)ethyl]-4-[2-(4-nitrophenyl)ethyl]piperazine Chemical compound C1=CC([N+](=O)[O-])=CC=C1CCN1CCN(CCC=2C=CC(Br)=CC=2)CC1 HATMFSKQAITDIR-UHFFFAOYSA-N 0.000 description 2
- SFKBOTCVPFRCEE-UHFFFAOYSA-N 1-[2-(4-nitrophenyl)ethyl]-4-[1-(4-nitrophenyl)propan-2-yl]piperazine Chemical compound C1CN(CCC=2C=CC(=CC=2)[N+]([O-])=O)CCN1C(C)CC1=CC=C([N+]([O-])=O)C=C1 SFKBOTCVPFRCEE-UHFFFAOYSA-N 0.000 description 2
- GQOXXKSNEOMYOB-UHFFFAOYSA-N 1-[2-(4-nitrophenyl)ethyl]-4-[2-(4-nitrophenyl)propyl]piperazine Chemical compound C=1C=C([N+]([O-])=O)C=CC=1C(C)CN(CC1)CCN1CCC1=CC=C([N+]([O-])=O)C=C1 GQOXXKSNEOMYOB-UHFFFAOYSA-N 0.000 description 2
- VLLHPXSNIWLSEW-UHFFFAOYSA-N 1-[2-(4-nitrophenyl)ethyl]-4-[2-[4-nitro-2-(trifluoromethyl)phenyl]ethyl]piperazine Chemical compound C1=CC([N+](=O)[O-])=CC=C1CCN1CCN(CCC=2C(=CC(=CC=2)[N+]([O-])=O)C(F)(F)F)CC1 VLLHPXSNIWLSEW-UHFFFAOYSA-N 0.000 description 2
- APTDRDYSJZQPPI-UHFFFAOYSA-N 1-bromo-4-(2-bromoethyl)benzene Chemical compound BrCCC1=CC=C(Br)C=C1 APTDRDYSJZQPPI-UHFFFAOYSA-N 0.000 description 2
- FOWKAELGOOICFQ-UHFFFAOYSA-N 1-formyl-2,3-dihydro-1h-indene-4-carbonitrile Chemical compound C1=CC=C(C#N)C2=C1C(C=O)CC2 FOWKAELGOOICFQ-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- WUCMNWFALWWMRK-UHFFFAOYSA-N 2,3,3-trimethyl-2-(4-methyl-1-oxo-3H-2-benzofuran-5-yl)butanoic acid Chemical compound C1=C(C(C)(C(O)=O)C(C)(C)C)C(C)=C2COC(=O)C2=C1 WUCMNWFALWWMRK-UHFFFAOYSA-N 0.000 description 2
- SPSCLZQHZBLDLY-UHFFFAOYSA-N 2,5-difluoro-4-(2-oxoethyl)benzonitrile Chemical compound FC1=CC(C#N)=C(F)C=C1CC=O SPSCLZQHZBLDLY-UHFFFAOYSA-N 0.000 description 2
- VHAIJULIGNWLAS-UHFFFAOYSA-N 2-(2,1,3-benzoxadiazol-5-yl)acetaldehyde Chemical compound C1=C(CC=O)C=CC2=NON=C21 VHAIJULIGNWLAS-UHFFFAOYSA-N 0.000 description 2
- MHXDEJQIKNIUQD-UHFFFAOYSA-N 2-(2-chloro-4-cyano-5-methoxyphenyl)acetic acid Chemical compound COC1=CC(CC(O)=O)=C(Cl)C=C1C#N MHXDEJQIKNIUQD-UHFFFAOYSA-N 0.000 description 2
- ZCJFKKAJDJUIOI-UHFFFAOYSA-N 2-(3-bromo-4-cyanophenyl)acetic acid Chemical compound OC(=O)CC1=CC=C(C#N)C(Br)=C1 ZCJFKKAJDJUIOI-UHFFFAOYSA-N 0.000 description 2
- RFTTZZZIURDXEQ-UHFFFAOYSA-N 2-(4-cyano-2,5-difluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC(F)=C(C#N)C=C1F RFTTZZZIURDXEQ-UHFFFAOYSA-N 0.000 description 2
- LQMHAQSWNXCDAX-UHFFFAOYSA-N 2-(7-oxo-6,8-dihydro-5h-naphthalen-2-yl)isoindole-1,3-dione Chemical compound C1CC(=O)CC2=CC(N3C(C4=CC=CC=C4C3=O)=O)=CC=C21 LQMHAQSWNXCDAX-UHFFFAOYSA-N 0.000 description 2
- ROLNEOWLZZGHSJ-UHFFFAOYSA-N 2-(difluoromethoxy)-4-[2-[4-[2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile Chemical compound CC1=C2COC(=O)C2=CC=C1CCN(CC1)CCN1CCC1=CC=C(C#N)C(OC(F)F)=C1 ROLNEOWLZZGHSJ-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- XHHWIDOJQIFJQS-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxymethyl]-1,4-bis[2-(4-nitrophenyl)ethyl]piperazine Chemical compound C1CN(CCC=2C=CC(=CC=2)[N+]([O-])=O)C(COC(C)(C)C)CN1CCC1=CC=C([N+]([O-])=O)C=C1 XHHWIDOJQIFJQS-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- NELVBTNXTWNSDB-UHFFFAOYSA-N 2-[4-cyano-3-(trifluoromethoxy)phenyl]acetic acid Chemical compound OC(=O)CC1=CC=C(C#N)C(OC(F)(F)F)=C1 NELVBTNXTWNSDB-UHFFFAOYSA-N 0.000 description 2
- XSWVQBHVHVYSBX-UHFFFAOYSA-N 2-[6-(tetrazol-1-yl)pyridin-3-yl]ethanol Chemical compound N1=CC(CCO)=CC=C1N1N=NN=C1 XSWVQBHVHVYSBX-UHFFFAOYSA-N 0.000 description 2
- UQVPDEBYQGXQSR-UHFFFAOYSA-N 2-bromo-4-(2-oxoethyl)benzonitrile Chemical compound BrC1=CC(CC=O)=CC=C1C#N UQVPDEBYQGXQSR-UHFFFAOYSA-N 0.000 description 2
- QIAOITGKSVWAFJ-UHFFFAOYSA-N 2-bromo-4-[2-[4-[2-(1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile Chemical compound C1=C(C#N)C(Br)=CC(CCN2CCN(CCC=3C=C4COC(=O)C4=CC=3)CC2)=C1 QIAOITGKSVWAFJ-UHFFFAOYSA-N 0.000 description 2
- YUXMSACGVRVROR-UHFFFAOYSA-N 2-cyclopropyloxy-4-(2-oxoethyl)benzonitrile Chemical compound O=CCC1=CC=C(C#N)C(OC2CC2)=C1 YUXMSACGVRVROR-UHFFFAOYSA-N 0.000 description 2
- HJNIFVJEIFDBNO-UHFFFAOYSA-N 2-ethenyl-5-nitropyridine Chemical compound [O-][N+](=O)C1=CC=C(C=C)N=C1 HJNIFVJEIFDBNO-UHFFFAOYSA-N 0.000 description 2
- IQNFTEUPMPWJAA-UHFFFAOYSA-N 2-fluoro-3-methyl-4-(2-oxoethyl)benzonitrile Chemical compound CC1=C(F)C(C#N)=CC=C1CC=O IQNFTEUPMPWJAA-UHFFFAOYSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- IOWGTMJAODHIJO-UHFFFAOYSA-N 2-methoxy-4-[1-[4-[2-(1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]propan-2-yl]benzonitrile Chemical compound C1=C(C#N)C(OC)=CC(C(C)CN2CCN(CCC=3C=C4COC(=O)C4=CC=3)CC2)=C1 IOWGTMJAODHIJO-UHFFFAOYSA-N 0.000 description 2
- CFAADJRDHYZYHJ-UHFFFAOYSA-N 2-methoxy-4-[2-[2-(trifluoromethyl)piperazin-1-yl]ethyl]benzonitrile Chemical compound C1=C(C#N)C(OC)=CC(CCN2C(CNCC2)C(F)(F)F)=C1 CFAADJRDHYZYHJ-UHFFFAOYSA-N 0.000 description 2
- HXFNCVGEEUQVOE-UHFFFAOYSA-N 2-methoxy-4-[2-[4-[2-(1-oxo-3h-2-benzofuran-5-yl)ethyl]-3-(trifluoromethyl)piperazin-1-yl]ethyl]benzonitrile Chemical compound C1=C(C#N)C(OC)=CC(CCN2CC(N(CCC=3C=C4COC(=O)C4=CC=3)CC2)C(F)(F)F)=C1 HXFNCVGEEUQVOE-UHFFFAOYSA-N 0.000 description 2
- NJBHRHHSGVGXMN-UHFFFAOYSA-N 2-methoxy-4-[2-[4-[2-(1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]propyl]benzonitrile Chemical compound C1=C(C#N)C(OC)=CC(CC(C)N2CCN(CCC=3C=C4COC(=O)C4=CC=3)CC2)=C1 NJBHRHHSGVGXMN-UHFFFAOYSA-N 0.000 description 2
- WQPCNHKENDXDBI-UHFFFAOYSA-N 2-methoxy-4-[2-[4-[2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]propyl]benzonitrile Chemical compound C1=C(C#N)C(OC)=CC(CC(C)N2CCN(CCC=3C(=C4COC(=O)C4=CC=3)C)CC2)=C1 WQPCNHKENDXDBI-UHFFFAOYSA-N 0.000 description 2
- ROHVZQDYFDDREK-UHFFFAOYSA-N 2-methoxy-4-[2-methyl-1-[4-[2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]propan-2-yl]benzonitrile Chemical compound C1=C(C#N)C(OC)=CC(C(C)(C)CN2CCN(CCC=3C(=C4COC(=O)C4=CC=3)C)CC2)=C1 ROHVZQDYFDDREK-UHFFFAOYSA-N 0.000 description 2
- VIQJSXAQBVGMHH-UHFFFAOYSA-N 2-methyl-1-[2-(4-nitrophenyl)ethyl]piperazine;hydrochloride Chemical compound Cl.CC1CNCCN1CCC1=CC=C([N+]([O-])=O)C=C1 VIQJSXAQBVGMHH-UHFFFAOYSA-N 0.000 description 2
- WWJXDZMWEJEKIH-UHFFFAOYSA-N 2-methyl-4-(2-oxoethyl)benzonitrile Chemical compound CC1=CC(CC=O)=CC=C1C#N WWJXDZMWEJEKIH-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- FLXCOBZXWCLUNJ-UHFFFAOYSA-N 3-methoxy-4-(2-oxoethyl)benzonitrile Chemical compound COC1=CC(C#N)=CC=C1CC=O FLXCOBZXWCLUNJ-UHFFFAOYSA-N 0.000 description 2
- SFRWCANJPATHPQ-UHFFFAOYSA-N 3-methyl-6-(2-piperazin-1-ylethyl)-3,4-dihydroisochromen-1-one;hydrochloride Chemical compound Cl.C=1C=C2C(=O)OC(C)CC2=CC=1CCN1CCNCC1 SFRWCANJPATHPQ-UHFFFAOYSA-N 0.000 description 2
- OLFOKKORDZFVJI-UHFFFAOYSA-N 3-o-tert-butyl 1-o-methyl 2-(2-chloro-4-cyano-3-fluorophenyl)propanedioate Chemical compound CC(C)(C)OC(=O)C(C(=O)OC)C1=CC=C(C#N)C(F)=C1Cl OLFOKKORDZFVJI-UHFFFAOYSA-N 0.000 description 2
- CXKADYCTKIATCM-UHFFFAOYSA-N 3-o-tert-butyl 1-o-methyl 2-(4-cyano-3-fluoro-2-methylphenyl)propanedioate Chemical compound CC(C)(C)OC(=O)C(C(=O)OC)C1=CC=C(C#N)C(F)=C1C CXKADYCTKIATCM-UHFFFAOYSA-N 0.000 description 2
- XPSYZCWYRWHVCC-UHFFFAOYSA-N 3-o-tert-butyl 1-o-methyl propanedioate Chemical compound COC(=O)CC(=O)OC(C)(C)C XPSYZCWYRWHVCC-UHFFFAOYSA-N 0.000 description 2
- ZYERAUDGKPMKSV-UHFFFAOYSA-N 4-(2-hydroxyethyl)naphthalene-1-carbonitrile Chemical compound C1=CC=C2C(CCO)=CC=C(C#N)C2=C1 ZYERAUDGKPMKSV-UHFFFAOYSA-N 0.000 description 2
- VSIRVVOMAHPZLW-UHFFFAOYSA-N 4-[2-[4-[2-(4-cyano-2-fluoro-5-methoxyphenyl)ethyl]piperazin-1-yl]ethyl]-5-fluoro-2-methoxybenzonitrile Chemical compound C1=C(C#N)C(OC)=CC(CCN2CCN(CCC=3C(=CC(=C(OC)C=3)C#N)F)CC2)=C1F VSIRVVOMAHPZLW-UHFFFAOYSA-N 0.000 description 2
- XPWXBGYLYLSHTG-UHFFFAOYSA-N 4-[2-[4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl]ethyl]benzonitrile Chemical compound C1=CC([N+](=O)[O-])=CC=C1CCN1CCN(CCC=2C=CC(=CC=2)C#N)CC1 XPWXBGYLYLSHTG-UHFFFAOYSA-N 0.000 description 2
- QRUOZMVYROKPOO-UHFFFAOYSA-N 4-bromo-2-methoxybenzonitrile Chemical compound COC1=CC(Br)=CC=C1C#N QRUOZMVYROKPOO-UHFFFAOYSA-N 0.000 description 2
- MNLZFMGQQIWADQ-UHFFFAOYSA-N 4-fluoro-2-methoxy-3-(2-oxoethyl)benzonitrile Chemical compound COC1=C(CC=O)C(F)=CC=C1C#N MNLZFMGQQIWADQ-UHFFFAOYSA-N 0.000 description 2
- KYLOKPZEIPCZPM-UHFFFAOYSA-N 4-fluoro-2-methoxy-5-prop-2-enylbenzonitrile Chemical compound COC1=CC(F)=C(CC=C)C=C1C#N KYLOKPZEIPCZPM-UHFFFAOYSA-N 0.000 description 2
- QQXDMWUGNPAANF-UHFFFAOYSA-N 4-fluoro-5-iodo-2-methoxybenzonitrile Chemical compound COC1=CC(F)=C(I)C=C1C#N QQXDMWUGNPAANF-UHFFFAOYSA-N 0.000 description 2
- FLAJXCLQNJIJIN-UHFFFAOYSA-N 4-methyl-5-(2-piperazin-1-ylethyl)-3h-2-benzofuran-1-one Chemical compound CC1=C2COC(=O)C2=CC=C1CCN1CCNCC1 FLAJXCLQNJIJIN-UHFFFAOYSA-N 0.000 description 2
- SEWIXNYQXNASBQ-UHFFFAOYSA-N 5-[2-[4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl]ethyl]-2,1,3-benzoxadiazole Chemical compound C1=CC([N+](=O)[O-])=CC=C1CCN1CCN(CCC2=CC3=NON=C3C=C2)CC1 SEWIXNYQXNASBQ-UHFFFAOYSA-N 0.000 description 2
- LJCOFEDAMMEFHX-UHFFFAOYSA-N 5-[2-[4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl]ethyl]-3h-2-benzofuran-1-one Chemical compound C1=CC([N+](=O)[O-])=CC=C1CCN1CCN(CCC=2C=C3COC(=O)C3=CC=2)CC1 LJCOFEDAMMEFHX-UHFFFAOYSA-N 0.000 description 2
- WWVBAWOYTBIMBF-UHFFFAOYSA-N 5-[2-[4-[2-[6-(tetrazol-1-yl)pyridin-3-yl]ethyl]piperazin-1-yl]ethyl]-3h-2-benzofuran-1-one Chemical compound C=1C=C2C(=O)OCC2=CC=1CCN(CC1)CCN1CCC(C=N1)=CC=C1N1C=NN=N1 WWVBAWOYTBIMBF-UHFFFAOYSA-N 0.000 description 2
- ZWDFFESFCIACQC-UHFFFAOYSA-N 5-bromo-2,1,3-benzoxadiazole Chemical compound C1=C(Br)C=CC2=NON=C21 ZWDFFESFCIACQC-UHFFFAOYSA-N 0.000 description 2
- GXEUWTFWIRADKO-UHFFFAOYSA-N 5-chloro-2-methoxy-4-[2-[4-[2-(1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile Chemical compound C1=C(C#N)C(OC)=CC(CCN2CCN(CCC=3C=C4COC(=O)C4=CC=3)CC2)=C1Cl GXEUWTFWIRADKO-UHFFFAOYSA-N 0.000 description 2
- IMTGKCRPORCYIG-UHFFFAOYSA-N 5-fluoro-2-methoxy-4-[2-[4-[2-(1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile Chemical compound C1=C(C#N)C(OC)=CC(CCN2CCN(CCC=3C=C4COC(=O)C4=CC=3)CC2)=C1F IMTGKCRPORCYIG-UHFFFAOYSA-N 0.000 description 2
- JPUQGUJABRBWHC-UHFFFAOYSA-N 5-fluoro-2-methoxy-4-[2-[4-[2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile Chemical compound C1=C(C#N)C(OC)=CC(CCN2CCN(CCC=3C(=C4COC(=O)C4=CC=3)C)CC2)=C1F JPUQGUJABRBWHC-UHFFFAOYSA-N 0.000 description 2
- RAUQHWZIGNDBDK-UHFFFAOYSA-N 5-fluoro-3-[[4-[2-(1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]methyl]-3,4-dihydro-2h-chromene-7-carbonitrile Chemical compound C1=C2C(=O)OCC2=CC(CCN2CCN(CC2)CC2COC=3C=C(C=C(C=3C2)F)C#N)=C1 RAUQHWZIGNDBDK-UHFFFAOYSA-N 0.000 description 2
- LTPQISPOQQDKAE-UHFFFAOYSA-N 6-[4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl]-5,6,7,8-tetrahydronaphthalene-2-carbonitrile Chemical compound C1=CC([N+](=O)[O-])=CC=C1CCN1CCN(C2CC3=CC=C(C=C3CC2)C#N)CC1 LTPQISPOQQDKAE-UHFFFAOYSA-N 0.000 description 2
- NWXBUXVTSQHYLS-UHFFFAOYSA-N 6-fluoro-4-oxo-2,3-dihydrochromene-7-carbonitrile Chemical compound O=C1CCOC2=C1C=C(F)C(C#N)=C2 NWXBUXVTSQHYLS-UHFFFAOYSA-N 0.000 description 2
- KCZDEYYVIJOTEC-UHFFFAOYSA-N 6-fluoro-7-hydroxy-2,3-dihydrochromen-4-one Chemical compound O1CCC(=O)C2=C1C=C(O)C(F)=C2 KCZDEYYVIJOTEC-UHFFFAOYSA-N 0.000 description 2
- 102100033056 ATP-sensitive inward rectifier potassium channel 1 Human genes 0.000 description 2
- UXOWGYHJODZGMF-QORCZRPOSA-N Aliskiren Chemical compound COCCCOC1=CC(C[C@@H](C[C@H](N)[C@@H](O)C[C@@H](C(C)C)C(=O)NCC(C)(C)C(N)=O)C(C)C)=CC=C1OC UXOWGYHJODZGMF-QORCZRPOSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 239000005977 Ethylene Substances 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 2
- RPTUSVTUFVMDQK-UHFFFAOYSA-N Hidralazin Chemical compound C1=CC=C2C(NN)=NN=CC2=C1 RPTUSVTUFVMDQK-UHFFFAOYSA-N 0.000 description 2
- 101000944272 Homo sapiens ATP-sensitive inward rectifier potassium channel 1 Proteins 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 108700010041 Nicotinic acid receptor Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 208000004880 Polyuria Diseases 0.000 description 2
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 description 2
- 241000720974 Protium Species 0.000 description 2
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 description 2
- 229940124639 Selective inhibitor Drugs 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- NZVCEFMISRQVBC-UHFFFAOYSA-N [1,4-bis[2-(4-nitrophenyl)ethyl]piperazin-2-yl]methanol Chemical compound C1CN(CCC=2C=CC(=CC=2)[N+]([O-])=O)C(CO)CN1CCC1=CC=C([N+]([O-])=O)C=C1 NZVCEFMISRQVBC-UHFFFAOYSA-N 0.000 description 2
- 230000009102 absorption Effects 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 238000012435 analytical chromatography Methods 0.000 description 2
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 230000001174 ascending effect Effects 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 229910001626 barium chloride Inorganic materials 0.000 description 2
- WDIHJSXYQDMJHN-UHFFFAOYSA-L barium chloride Chemical compound [Cl-].[Cl-].[Ba+2] WDIHJSXYQDMJHN-UHFFFAOYSA-L 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 230000005587 bubbling Effects 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 235000010216 calcium carbonate Nutrition 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 235000011089 carbon dioxide Nutrition 0.000 description 2
- 229940125400 channel inhibitor Drugs 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 238000010367 cloning Methods 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 230000001054 cortical effect Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 229910052805 deuterium Inorganic materials 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- CLPHAYNBNTVRDI-UHFFFAOYSA-N ditert-butyl propanedioate Chemical compound CC(C)(C)OC(=O)CC(=O)OC(C)(C)C CLPHAYNBNTVRDI-UHFFFAOYSA-N 0.000 description 2
- 230000035619 diuresis Effects 0.000 description 2
- 238000000132 electrospray ionisation Methods 0.000 description 2
- UPJSNCXXJAWKLT-UHFFFAOYSA-N ethyl 2-(4-cyano-3-methoxyphenyl)propanoate Chemical compound CCOC(=O)C(C)C1=CC=C(C#N)C(OC)=C1 UPJSNCXXJAWKLT-UHFFFAOYSA-N 0.000 description 2
- KDMXMHFNHCXQAS-UHFFFAOYSA-N ethyl 3-(4-cyano-3-methylphenyl)oxirane-2-carboxylate Chemical compound CCOC(=O)C1OC1C1=CC=C(C#N)C(C)=C1 KDMXMHFNHCXQAS-UHFFFAOYSA-N 0.000 description 2
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 150000003840 hydrochlorides Chemical class 0.000 description 2
- 229960002003 hydrochlorothiazide Drugs 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 2
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 125000002346 iodo group Chemical group I* 0.000 description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229940057995 liquid paraffin Drugs 0.000 description 2
- PSIFNNKUMBGKDQ-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2NN=NN=2)C=C1 PSIFNNKUMBGKDQ-UHFFFAOYSA-N 0.000 description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 2
- 229960003105 metformin Drugs 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- FNGKOOQBUNGABP-NRFANRHFSA-N methyl (2s)-3-(4-nitrophenyl)-2-[4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl]propanoate Chemical compound C([C@@H](C(=O)OC)N1CCN(CCC=2C=CC(=CC=2)[N+]([O-])=O)CC1)C1=CC=C([N+]([O-])=O)C=C1 FNGKOOQBUNGABP-NRFANRHFSA-N 0.000 description 2
- QEQWDGVJDYRTFU-UHFFFAOYSA-N methyl 2-(2-chloro-4-cyano-3-methoxyphenyl)acetate Chemical compound COC(=O)CC1=CC=C(C#N)C(OC)=C1Cl QEQWDGVJDYRTFU-UHFFFAOYSA-N 0.000 description 2
- QMUKYDFVUQEZBC-UHFFFAOYSA-N methyl 2-(2-chloro-4-cyano-5-fluorophenyl)acetate Chemical compound COC(=O)CC1=CC(F)=C(C#N)C=C1Cl QMUKYDFVUQEZBC-UHFFFAOYSA-N 0.000 description 2
- FOQKSWFJLLJOLM-UHFFFAOYSA-N methyl 2-(2-chloro-4-cyano-5-methoxyphenyl)acetate Chemical compound COC(=O)CC1=CC(OC)=C(C#N)C=C1Cl FOQKSWFJLLJOLM-UHFFFAOYSA-N 0.000 description 2
- AXONPFSLAZILIE-UHFFFAOYSA-N methyl 2-(3-fluoro-4-hydroxyphenyl)acetate Chemical compound COC(=O)CC1=CC=C(O)C(F)=C1 AXONPFSLAZILIE-UHFFFAOYSA-N 0.000 description 2
- AXNOSUMFIOZSSF-UHFFFAOYSA-N methyl 2-(4-cyano-3-methoxy-2-methylphenyl)acetate Chemical compound COC(=O)CC1=CC=C(C#N)C(OC)=C1C AXNOSUMFIOZSSF-UHFFFAOYSA-N 0.000 description 2
- RUZFUOVOWFKADD-UHFFFAOYSA-N methyl 2-[1,4-bis[2-(4-nitrophenyl)ethyl]piperazin-2-yl]acetate Chemical compound C1CN(CCC=2C=CC(=CC=2)[N+]([O-])=O)C(CC(=O)OC)CN1CCC1=CC=C([N+]([O-])=O)C=C1 RUZFUOVOWFKADD-UHFFFAOYSA-N 0.000 description 2
- DHAQFVCHYRFSMG-UHFFFAOYSA-N methyl 2-[4-cyano-3-(trifluoromethoxy)phenyl]acetate Chemical compound COC(=O)CC1=CC=C(C#N)C(OC(F)(F)F)=C1 DHAQFVCHYRFSMG-UHFFFAOYSA-N 0.000 description 2
- 229960002237 metoprolol Drugs 0.000 description 2
- IUBSYMUCCVWXPE-UHFFFAOYSA-N metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- HHQJWDKIRXRTLS-UHFFFAOYSA-N n'-bromobutanediamide Chemical compound NC(=O)CCC(=O)NBr HHQJWDKIRXRTLS-UHFFFAOYSA-N 0.000 description 2
- 229960003512 nicotinic acid Drugs 0.000 description 2
- 235000001968 nicotinic acid Nutrition 0.000 description 2
- 239000011664 nicotinic acid Substances 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 235000008390 olive oil Nutrition 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 238000005949 ozonolysis reaction Methods 0.000 description 2
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 2
- 239000012466 permeate Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- WLJVNTCWHIRURA-UHFFFAOYSA-N pimelic acid Chemical compound OC(=O)CCCCCC(O)=O WLJVNTCWHIRURA-UHFFFAOYSA-N 0.000 description 2
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000010926 purge Methods 0.000 description 2
- 239000002461 renin inhibitor Substances 0.000 description 2
- 229940086526 renin-inhibitors Drugs 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 229960004034 sitagliptin Drugs 0.000 description 2
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 235000010265 sodium sulphite Nutrition 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 238000004808 supercritical fluid chromatography Methods 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- WCGKHZHOGLVVPU-UHFFFAOYSA-N tert-butyl 3-(trifluoromethyl)piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNC(C(F)(F)F)C1 WCGKHZHOGLVVPU-UHFFFAOYSA-N 0.000 description 2
- PWSJLLJLKJWJAE-UHFFFAOYSA-N tert-butyl 4-(5-bromo-2,3-dihydro-1h-inden-2-yl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1CC2=CC(Br)=CC=C2C1 PWSJLLJLKJWJAE-UHFFFAOYSA-N 0.000 description 2
- JNVNRVMWDBZNON-UHFFFAOYSA-N tert-butyl 4-(5-cyano-2,3-dihydro-1h-inden-2-yl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1CC2=CC(C#N)=CC=C2C1 JNVNRVMWDBZNON-UHFFFAOYSA-N 0.000 description 2
- GUXGPTAEJXGABG-UHFFFAOYSA-N tert-butyl 4-[2-(2,1,3-benzoxadiazol-5-yl)ethyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1CCC1=CC2=NON=C2C=C1 GUXGPTAEJXGABG-UHFFFAOYSA-N 0.000 description 2
- UQPFMRBSBDGHSJ-UHFFFAOYSA-N tert-butyl 4-[2-(4-cyano-3-methylsulfanylphenyl)ethyl]piperazine-1-carboxylate Chemical compound C1=C(C#N)C(SC)=CC(CCN2CCN(CC2)C(=O)OC(C)(C)C)=C1 UQPFMRBSBDGHSJ-UHFFFAOYSA-N 0.000 description 2
- LHANJBOZCKYPIZ-UHFFFAOYSA-N tert-butyl 4-[2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)propyl]piperazine-1-carboxylate Chemical compound C=1C=C2C(=O)OCC2=C(C)C=1C(C)CN1CCN(C(=O)OC(C)(C)C)CC1 LHANJBOZCKYPIZ-UHFFFAOYSA-N 0.000 description 2
- YIUGMVHOHIXRJH-AWEZNQCLSA-N tert-butyl N-[(2S)-6-cyano-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate Chemical compound N#CC1=CC=C2C[C@@H](NC(=O)OC(C)(C)C)CCC2=C1 YIUGMVHOHIXRJH-AWEZNQCLSA-N 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 2
- 239000002562 thickening agent Substances 0.000 description 2
- 230000036962 time dependent Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 2
- 238000000825 ultraviolet detection Methods 0.000 description 2
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 1
- ISYQWKOXKGJREA-RSLHMRQOSA-N (1s,4s)-2,5-diazabicyclo[2.2.1]heptane;dihydrobromide Chemical compound Br.Br.C1N[C@@H]2CN[C@H]1C2 ISYQWKOXKGJREA-RSLHMRQOSA-N 0.000 description 1
- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 description 1
- QIJLJZOGPPQCOG-NFAWXSAZSA-N (2s)-1-[(2s)-3-[(2r)-2-(cyclohexanecarbonylamino)propanoyl]sulfanyl-2-methylpropanoyl]pyrrolidine-2-carboxylic acid Chemical compound N([C@H](C)C(=O)SC[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)C(=O)C1CCCCC1 QIJLJZOGPPQCOG-NFAWXSAZSA-N 0.000 description 1
- BIDNLKIUORFRQP-XYGFDPSESA-N (2s,4s)-4-cyclohexyl-1-[2-[[(1s)-2-methyl-1-propanoyloxypropoxy]-(4-phenylbutyl)phosphoryl]acetyl]pyrrolidine-2-carboxylic acid Chemical compound C([P@@](=O)(O[C@H](OC(=O)CC)C(C)C)CC(=O)N1[C@@H](C[C@H](C1)C1CCCCC1)C(O)=O)CCCC1=CC=CC=C1 BIDNLKIUORFRQP-XYGFDPSESA-N 0.000 description 1
- FQXNEJZEPHQHEK-LURJTMIESA-N (3s)-6-bromo-3-methyl-3,4-dihydroisochromen-1-one Chemical compound BrC1=CC=C2C(=O)O[C@@H](C)CC2=C1 FQXNEJZEPHQHEK-LURJTMIESA-N 0.000 description 1
- IYZRFOAPEUBNQP-JPZLKUPGSA-N (3s)-n-[(2s)-1-[[(5s)-5-amino-6-hydroxyhexyl]amino]-4-methyl-1-oxopentan-2-yl]-3-hydroxy-4-[[3-(1h-imidazol-5-yl)-2-[[3-naphthalen-1-yl-2-(naphthalen-1-ylmethyl)propanoyl]amino]propanoyl]amino]-6-methylheptanamide;dihydrochloride Chemical compound Cl.Cl.C=1C=CC2=CC=CC=C2C=1CC(CC=1C2=CC=CC=C2C=CC=1)C(=O)NC(C(=O)NC(CC(C)C)[C@@H](O)CC(=O)N[C@@H](CC(C)C)C(=O)NCCCC[C@H](N)CO)CC1=CN=CN1 IYZRFOAPEUBNQP-JPZLKUPGSA-N 0.000 description 1
- SYPWPWUSXPWLKW-ZQWQDMLBSA-N (3s,4s)-5-cyclohexyl-n-hexyl-3-hydroxy-4-[[(2s)-2-[[(2s)-2-[(2-morpholin-4-ylacetyl)amino]-3-naphthalen-1-ylpropanoyl]amino]-3-(1,3-thiazol-4-yl)propanoyl]amino]pentanamide Chemical compound C([C@@H]([C@@H](O)CC(=O)NCCCCCC)NC(=O)[C@H](CC=1N=CSC=1)NC(=O)[C@H](CC=1C2=CC=CC=C2C=CC=1)NC(=O)CN1CCOCC1)C1CCCCC1 SYPWPWUSXPWLKW-ZQWQDMLBSA-N 0.000 description 1
- METKIMKYRPQLGS-GFCCVEGCSA-N (R)-atenolol Chemical compound CC(C)NC[C@@H](O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-GFCCVEGCSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- TUASUSQCFYRALM-UHFFFAOYSA-N 1-(5-nitro-2,3-dihydro-1h-inden-2-yl)-4-[2-(4-nitrophenyl)ethyl]piperazine Chemical compound C1=CC([N+](=O)[O-])=CC=C1CCN1CCN(C2CC3=CC(=CC=C3C2)[N+]([O-])=O)CC1 TUASUSQCFYRALM-UHFFFAOYSA-N 0.000 description 1
- YYXORWQVAWKELM-UHFFFAOYSA-N 1-[2-(4-nitrophenyl)ethyl]-4-[2-(5-nitropyridin-2-yl)ethyl]piperazine Chemical compound C1=CC([N+](=O)[O-])=CC=C1CCN1CCN(CCC=2N=CC(=CC=2)[N+]([O-])=O)CC1 YYXORWQVAWKELM-UHFFFAOYSA-N 0.000 description 1
- LDHDLZVIOVDTCH-UHFFFAOYSA-N 1-[2-(4-nitrophenyl)ethyl]piperazine Chemical compound C1=CC([N+](=O)[O-])=CC=C1CCN1CCNCC1 LDHDLZVIOVDTCH-UHFFFAOYSA-N 0.000 description 1
- WABIREPHBJRZAE-UHFFFAOYSA-N 1-[[4-[2-(1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]methyl]-2,3-dihydro-1h-indene-4-carbonitrile Chemical compound C1CC(C(=CC=C2)C#N)=C2C1CN(CC1)CCN1CCC1=CC=C2C(=O)OCC2=C1 WABIREPHBJRZAE-UHFFFAOYSA-N 0.000 description 1
- LOWVLPPNCBVKHM-UHFFFAOYSA-N 1-[[4-[2-(3-oxo-1h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]methyl]-2,3-dihydro-1h-indene-4-carbonitrile Chemical compound C1CC(C(=CC=C2)C#N)=C2C1CN(CC1)CCN1CCC1=CC=C2COC(=O)C2=C1 LOWVLPPNCBVKHM-UHFFFAOYSA-N 0.000 description 1
- IVVNZDGDKPTYHK-JTQLQIEISA-N 1-cyano-2-[(2s)-3,3-dimethylbutan-2-yl]-3-pyridin-4-ylguanidine Chemical compound CC(C)(C)[C@H](C)N=C(NC#N)NC1=CC=NC=C1 IVVNZDGDKPTYHK-JTQLQIEISA-N 0.000 description 1
- PIPWSBOFSUJCCO-UHFFFAOYSA-N 2,2-dimethylpiperazine Chemical compound CC1(C)CNCCN1 PIPWSBOFSUJCCO-UHFFFAOYSA-N 0.000 description 1
- DLKNOGQOOZFICZ-UHFFFAOYSA-N 2,4,5-trifluorobenzonitrile Chemical compound FC1=CC(F)=C(C#N)C=C1F DLKNOGQOOZFICZ-UHFFFAOYSA-N 0.000 description 1
- BRPIQWMBLBJUDZ-UHFFFAOYSA-N 2,5-bis[2-(4-nitrophenyl)ethyl]-2,5-diazabicyclo[2.2.2]octane Chemical compound C1=CC([N+](=O)[O-])=CC=C1CCN1C(CN2CCC=3C=CC(=CC=3)[N+]([O-])=O)CCC2C1 BRPIQWMBLBJUDZ-UHFFFAOYSA-N 0.000 description 1
- QOFATPWEHYVHFQ-UHFFFAOYSA-N 2,5-difluoro-4-[2-[4-[2-(1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile Chemical compound FC1=CC(C#N)=C(F)C=C1CCN1CCN(CCC=2C=C3COC(=O)C3=CC=2)CC1 QOFATPWEHYVHFQ-UHFFFAOYSA-N 0.000 description 1
- BDKNFJUXHNDFDF-UHFFFAOYSA-N 2,6-difluoro-4-(2-oxoethyl)benzonitrile Chemical compound FC1=CC(CC=O)=CC(F)=C1C#N BDKNFJUXHNDFDF-UHFFFAOYSA-N 0.000 description 1
- XUSKZLBLGHBCLD-UHFFFAOYSA-N 2-(3-aminophenyl)acetic acid Chemical compound NC1=CC=CC(CC(O)=O)=C1 XUSKZLBLGHBCLD-UHFFFAOYSA-N 0.000 description 1
- CINFDMVPHNPKFR-UHFFFAOYSA-N 2-(3-chloro-4-cyanophenyl)acetic acid Chemical compound OC(=O)CC1=CC=C(C#N)C(Cl)=C1 CINFDMVPHNPKFR-UHFFFAOYSA-N 0.000 description 1
- YRFBZAHYMOSSGX-UHFFFAOYSA-N 2-(3-fluoro-4-hydroxyphenyl)acetic acid Chemical compound OC(=O)CC1=CC=C(O)C(F)=C1 YRFBZAHYMOSSGX-UHFFFAOYSA-N 0.000 description 1
- FMUXZOPOCJDVNE-UHFFFAOYSA-N 2-(4-cyano-2,3,6-trifluorophenyl)acetic acid Chemical compound OC(=O)CC1=C(F)C=C(C#N)C(F)=C1F FMUXZOPOCJDVNE-UHFFFAOYSA-N 0.000 description 1
- YIZAIUFAZJFBOP-UHFFFAOYSA-N 2-(4-cyano-2-fluoro-3-methoxyphenyl)acetic acid Chemical compound COC1=C(F)C(CC(O)=O)=CC=C1C#N YIZAIUFAZJFBOP-UHFFFAOYSA-N 0.000 description 1
- WMNIMNHDKXPJPF-UHFFFAOYSA-N 2-(4-cyano-3-ethoxyphenyl)acetic acid Chemical compound CCOC1=CC(CC(O)=O)=CC=C1C#N WMNIMNHDKXPJPF-UHFFFAOYSA-N 0.000 description 1
- OCZPYSNNNSFVMP-UHFFFAOYSA-N 2-(4-cyanonaphthalen-1-yl)acetic acid Chemical compound C1=CC=C2C(CC(=O)O)=CC=C(C#N)C2=C1 OCZPYSNNNSFVMP-UHFFFAOYSA-N 0.000 description 1
- HLXWNWCSCDRARL-UHFFFAOYSA-N 2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)acetaldehyde Chemical compound C1=C(CC=O)C(C)=C2COC(=O)C2=C1 HLXWNWCSCDRARL-UHFFFAOYSA-N 0.000 description 1
- RBSRRICSXWXMRC-UHFFFAOYSA-N 2-(4-nitrophenyl)propanoic acid Chemical compound OC(=O)C(C)C1=CC=C([N+]([O-])=O)C=C1 RBSRRICSXWXMRC-UHFFFAOYSA-N 0.000 description 1
- IBCHCVUAXFASOU-UHFFFAOYSA-N 2-(difluoromethoxy)-4-(2-oxoethyl)benzonitrile Chemical compound FC(F)OC1=CC(CC=O)=CC=C1C#N IBCHCVUAXFASOU-UHFFFAOYSA-N 0.000 description 1
- LSJNKPZBPMZYDR-UHFFFAOYSA-N 2-(difluoromethoxy)-4-[2-[4-[2-(1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile Chemical compound C1=C(C#N)C(OC(F)F)=CC(CCN2CCN(CCC=3C=C4COC(=O)C4=CC=3)CC2)=C1 LSJNKPZBPMZYDR-UHFFFAOYSA-N 0.000 description 1
- VLMKSZTVRLMNFJ-UHFFFAOYSA-N 2-(difluoromethyl)-1,4-bis[2-(4-nitrophenyl)ethyl]piperazine Chemical compound C1=CC([N+](=O)[O-])=CC=C1CCN1CC(C(F)F)N(CCC=2C=CC(=CC=2)[N+]([O-])=O)CC1 VLMKSZTVRLMNFJ-UHFFFAOYSA-N 0.000 description 1
- GNCDPUYXABYJAU-UHFFFAOYSA-N 2-(difluoromethyl)piperazine Chemical compound FC(F)C1CNCCN1 GNCDPUYXABYJAU-UHFFFAOYSA-N 0.000 description 1
- OXQGTIUCKGYOAA-UHFFFAOYSA-N 2-Ethylbutanoic acid Chemical compound CCC(CC)C(O)=O OXQGTIUCKGYOAA-UHFFFAOYSA-N 0.000 description 1
- ITPDXMSMCXRJLO-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxymethyl]piperazine-1,4-diium;diacetate Chemical compound CC([O-])=O.CC([O-])=O.CC(C)(C)OCC1C[NH2+]CC[NH2+]1 ITPDXMSMCXRJLO-UHFFFAOYSA-N 0.000 description 1
- ZZRFQBQNZLFESZ-BTQNPOSSSA-N 2-[(3r)-4-[(4-chlorophenyl)methyl]-7-fluoro-5-methylsulfonyl-2,3-dihydro-1h-cyclopenta[b]indol-3-yl]acetic acid;pyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=CN=C1.C=1([C@@H](CC(O)=O)CCC=1C=1C=C(F)C=C(C2=1)S(=O)(=O)C)N2CC1=CC=C(Cl)C=C1 ZZRFQBQNZLFESZ-BTQNPOSSSA-N 0.000 description 1
- OGYBWZMCGUWWHS-UHFFFAOYSA-N 2-[4-(tetrazol-1-yl)phenyl]acetic acid Chemical compound C1=CC(CC(=O)O)=CC=C1N1N=NN=C1 OGYBWZMCGUWWHS-UHFFFAOYSA-N 0.000 description 1
- LIEFWTUAXOUFOO-UHFFFAOYSA-N 2-[4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl]-2,3-dihydro-1h-indene-5-carbonitrile Chemical compound C1=CC([N+](=O)[O-])=CC=C1CCN1CCN(C2CC3=CC(=CC=C3C2)C#N)CC1 LIEFWTUAXOUFOO-UHFFFAOYSA-N 0.000 description 1
- MNNDREXLRLDWEY-UHFFFAOYSA-N 2-bromo-4-fluorobenzonitrile Chemical compound FC1=CC=C(C#N)C(Br)=C1 MNNDREXLRLDWEY-UHFFFAOYSA-N 0.000 description 1
- HUUFTVUBFFESEN-UHFFFAOYSA-N 2-bromo-5-nitropyridine Chemical compound [O-][N+](=O)C1=CC=C(Br)N=C1 HUUFTVUBFFESEN-UHFFFAOYSA-N 0.000 description 1
- SDFXSBFOVNINTE-UHFFFAOYSA-N 2-chloro-4-[2-[4-[2-(1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile Chemical compound C1=C(C#N)C(Cl)=CC(CCN2CCN(CCC=3C=C4COC(=O)C4=CC=3)CC2)=C1 SDFXSBFOVNINTE-UHFFFAOYSA-N 0.000 description 1
- KMODYEIPCVNXAI-UHFFFAOYSA-N 2-chloro-4-[2-[4-[2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile Chemical compound CC1=C2COC(=O)C2=CC=C1CCN(CC1)CCN1CCC1=CC=C(C#N)C(Cl)=C1 KMODYEIPCVNXAI-UHFFFAOYSA-N 0.000 description 1
- FUTJIVFKLDPOQM-UHFFFAOYSA-N 2-cyclopropyl-1,4-bis[2-(4-nitrophenyl)ethyl]piperazine Chemical compound C1=CC([N+](=O)[O-])=CC=C1CCN1CC(C2CC2)N(CCC=2C=CC(=CC=2)[N+]([O-])=O)CC1 FUTJIVFKLDPOQM-UHFFFAOYSA-N 0.000 description 1
- SXGUFQFMTFDRMC-UHFFFAOYSA-N 2-cyclopropylpiperazine Chemical compound C1CC1C1NCCNC1 SXGUFQFMTFDRMC-UHFFFAOYSA-N 0.000 description 1
- ZOYBCKDSOSQMLT-UHFFFAOYSA-N 2-ethoxy-4-[2-[4-[2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile Chemical compound C1=C(C#N)C(OCC)=CC(CCN2CCN(CCC=3C(=C4COC(=O)C4=CC=3)C)CC2)=C1 ZOYBCKDSOSQMLT-UHFFFAOYSA-N 0.000 description 1
- GQHGXIIHBJOTCV-UHFFFAOYSA-N 2-fluoro-3-methyl-4-[2-[4-[2-(1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile Chemical compound CC1=C(F)C(C#N)=CC=C1CCN1CCN(CCC=2C=C3COC(=O)C3=CC=2)CC1 GQHGXIIHBJOTCV-UHFFFAOYSA-N 0.000 description 1
- XGGCQNBAJBIQOY-UHFFFAOYSA-N 2-fluoro-3-methyl-4-[2-[4-[2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile Chemical compound CC1=C2COC(=O)C2=CC=C1CCN(CC1)CCN1CCC1=CC=C(C#N)C(F)=C1C XGGCQNBAJBIQOY-UHFFFAOYSA-N 0.000 description 1
- JSEAAWWRMQUDJU-UHFFFAOYSA-N 2-fluoro-4-[2-[4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl]ethyl]benzonitrile Chemical compound C1=CC([N+](=O)[O-])=CC=C1CCN1CCN(CCC=2C=C(F)C(C#N)=CC=2)CC1 JSEAAWWRMQUDJU-UHFFFAOYSA-N 0.000 description 1
- HZIBQWMVWMZYPL-UHFFFAOYSA-N 2-methoxy-3-methyl-4-[2-[4-[2-(1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile Chemical compound C1=C(C#N)C(OC)=C(C)C(CCN2CCN(CCC=3C=C4COC(=O)C4=CC=3)CC2)=C1 HZIBQWMVWMZYPL-UHFFFAOYSA-N 0.000 description 1
- VSFYZQDCIYHPMA-UHFFFAOYSA-N 2-methoxy-3-methyl-4-[2-[4-[2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile Chemical compound C1=C(C#N)C(OC)=C(C)C(CCN2CCN(CCC=3C(=C4COC(=O)C4=CC=3)C)CC2)=C1 VSFYZQDCIYHPMA-UHFFFAOYSA-N 0.000 description 1
- FOIUHMWZDCXFLU-UHFFFAOYSA-N 2-methoxy-4-[1-[4-[2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]propan-2-yl]benzonitrile Chemical compound C1=C(C#N)C(OC)=CC(C(C)CN2CCN(CCC=3C(=C4COC(=O)C4=CC=3)C)CC2)=C1 FOIUHMWZDCXFLU-UHFFFAOYSA-N 0.000 description 1
- FPDPXFUWNGLVNF-UHFFFAOYSA-N 2-methoxy-4-[2-[4-[2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)propyl]piperazin-1-yl]ethyl]benzonitrile Chemical compound C1=C(C#N)C(OC)=CC(CCN2CCN(CC(C)C=3C(=C4COC(=O)C4=CC=3)C)CC2)=C1 FPDPXFUWNGLVNF-UHFFFAOYSA-N 0.000 description 1
- WAIUZUYUUVFKFO-UHFFFAOYSA-N 2-methoxy-4-[2-[4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl]ethyl]benzonitrile Chemical compound C1=C(C#N)C(OC)=CC(CCN2CCN(CCC=3C=CC(=CC=3)[N+]([O-])=O)CC2)=C1 WAIUZUYUUVFKFO-UHFFFAOYSA-N 0.000 description 1
- AOWSHKSCOCMIOV-UHFFFAOYSA-N 2-methyl-1,4-bis[2-(4-nitrophenyl)ethyl]piperazine Chemical compound C1CN(CCC=2C=CC(=CC=2)[N+]([O-])=O)C(C)CN1CCC1=CC=C([N+]([O-])=O)C=C1 AOWSHKSCOCMIOV-UHFFFAOYSA-N 0.000 description 1
- PMYURHZQDWMWOX-UHFFFAOYSA-N 2-methyl-4-[2-[4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl]ethyl]benzonitrile Chemical compound C1=C(C#N)C(C)=CC(CCN2CCN(CCC=3C=CC(=CC=3)[N+]([O-])=O)CC2)=C1 PMYURHZQDWMWOX-UHFFFAOYSA-N 0.000 description 1
- VGFMACKERBURQC-UHFFFAOYSA-N 2-methylsulfanyl-4-(2-piperazin-1-ylethyl)benzonitrile Chemical compound C1=C(C#N)C(SC)=CC(CCN2CCNCC2)=C1 VGFMACKERBURQC-UHFFFAOYSA-N 0.000 description 1
- HXVNLBDKDPCJNH-UHFFFAOYSA-N 2-methylsulfanyl-4-[2-[4-[2-(1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile Chemical compound C1=C(C#N)C(SC)=CC(CCN2CCN(CCC=3C=C4COC(=O)C4=CC=3)CC2)=C1 HXVNLBDKDPCJNH-UHFFFAOYSA-N 0.000 description 1
- KFTYFTKODBWKOU-UHFFFAOYSA-N 2-methylsulfonylethanol Chemical compound CS(=O)(=O)CCO KFTYFTKODBWKOU-UHFFFAOYSA-N 0.000 description 1
- ZNPZERUYWSMFQK-UHFFFAOYSA-N 3,8-bis[2-(4-nitrophenyl)ethyl]-3,8-diazabicyclo[3.2.1]octane Chemical compound C1=CC([N+](=O)[O-])=CC=C1CCN1C2CCC1CN(CCC=1C=CC(=CC=1)[N+]([O-])=O)C2 ZNPZERUYWSMFQK-UHFFFAOYSA-N 0.000 description 1
- LKDJYZBKCVSODK-UHFFFAOYSA-N 3,8-diazabicyclo[3.2.1]octane Chemical compound C1NCC2CCC1N2 LKDJYZBKCVSODK-UHFFFAOYSA-N 0.000 description 1
- NIZGVUZUYIGKRF-UHFFFAOYSA-N 3-(4-cyano-3-methylphenyl)oxirane-2-carboxylic acid Chemical compound C1=C(C#N)C(C)=CC(C2C(O2)C(O)=O)=C1 NIZGVUZUYIGKRF-UHFFFAOYSA-N 0.000 description 1
- BJGKVCKGUBYULR-UHFFFAOYSA-N 3-bromo-2-methylbenzoic acid Chemical compound CC1=C(Br)C=CC=C1C(O)=O BJGKVCKGUBYULR-UHFFFAOYSA-N 0.000 description 1
- KLOCIJDNSZBMDU-UHFFFAOYSA-N 3-chloro-2-fluoro-4-(2-hydroxyethyl)benzonitrile Chemical compound OCCC1=CC=C(C#N)C(F)=C1Cl KLOCIJDNSZBMDU-UHFFFAOYSA-N 0.000 description 1
- VOUWFNDKBBFCID-UHFFFAOYSA-N 3-chloro-2-fluoro-4-[2-[4-[2-(1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile Chemical compound C1=C(C#N)C(F)=C(Cl)C(CCN2CCN(CCC=3C=C4COC(=O)C4=CC=3)CC2)=C1 VOUWFNDKBBFCID-UHFFFAOYSA-N 0.000 description 1
- XIAVQTKOGMRVCP-UHFFFAOYSA-N 3-chloro-2-methoxy-4-[2-[4-[2-(1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile Chemical compound C1=C(C#N)C(OC)=C(Cl)C(CCN2CCN(CCC=3C=C4COC(=O)C4=CC=3)CC2)=C1 XIAVQTKOGMRVCP-UHFFFAOYSA-N 0.000 description 1
- XPYMHYHMIUPRSJ-UHFFFAOYSA-N 3-chloro-2-methoxy-4-[2-[4-[2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile Chemical compound C1=C(C#N)C(OC)=C(Cl)C(CCN2CCN(CCC=3C(=C4COC(=O)C4=CC=3)C)CC2)=C1 XPYMHYHMIUPRSJ-UHFFFAOYSA-N 0.000 description 1
- QEYMMOKECZBKAC-UHFFFAOYSA-N 3-chloropropanoic acid Chemical compound OC(=O)CCCl QEYMMOKECZBKAC-UHFFFAOYSA-N 0.000 description 1
- KZYWLWBNFZZDJW-UHFFFAOYSA-N 3-fluoro-2-methoxy-4-[2-[4-[2-(1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile Chemical compound C1=C(C#N)C(OC)=C(F)C(CCN2CCN(CCC=3C=C4COC(=O)C4=CC=3)CC2)=C1 KZYWLWBNFZZDJW-UHFFFAOYSA-N 0.000 description 1
- JKCOMOXVYVPGLI-UHFFFAOYSA-N 3-fluoro-2-methoxy-4-[2-[4-[2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile Chemical compound C1=C(C#N)C(OC)=C(F)C(CCN2CCN(CCC=3C(=C4COC(=O)C4=CC=3)C)CC2)=C1 JKCOMOXVYVPGLI-UHFFFAOYSA-N 0.000 description 1
- VYMKAWXMQGILPD-UHFFFAOYSA-N 3-methyl-4-(2-oxoethyl)benzonitrile Chemical compound CC1=CC(C#N)=CC=C1CC=O VYMKAWXMQGILPD-UHFFFAOYSA-N 0.000 description 1
- ZQOVRBSSXRZSIB-UHFFFAOYSA-N 3-methyl-4-[2-[4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl]ethyl]benzonitrile Chemical compound CC1=CC(C#N)=CC=C1CCN1CCN(CCC=2C=CC(=CC=2)[N+]([O-])=O)CC1 ZQOVRBSSXRZSIB-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- WINUGFPQSQQSHW-UHFFFAOYSA-N 3-tert-butyl-1,1-di(propan-2-yl)urea Chemical compound CC(C)N(C(C)C)C(=O)NC(C)(C)C WINUGFPQSQQSHW-UHFFFAOYSA-N 0.000 description 1
- BTDMXRCUNUVYDT-UHFFFAOYSA-N 4-(2-oxoethyl)benzonitrile Chemical compound O=CCC1=CC=C(C#N)C=C1 BTDMXRCUNUVYDT-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- SWLAMJPTOQZTAE-UHFFFAOYSA-N 4-[2-[(5-chloro-2-methoxybenzoyl)amino]ethyl]benzoic acid Chemical class COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(C(O)=O)C=C1 SWLAMJPTOQZTAE-UHFFFAOYSA-N 0.000 description 1
- AHSUYCYLWIKZAW-UHFFFAOYSA-N 4-[2-[4-[2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]-2-(trifluoromethoxy)benzonitrile Chemical compound CC1=C2COC(=O)C2=CC=C1CCN(CC1)CCN1CCC1=CC=C(C#N)C(OC(F)(F)F)=C1 AHSUYCYLWIKZAW-UHFFFAOYSA-N 0.000 description 1
- KTYDIPNIYXIARN-UHFFFAOYSA-N 4-[[4-[2-(1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]methyl]-3,4-dihydro-2h-chromene-7-carbonitrile Chemical compound C1COC2=CC(C#N)=CC=C2C1CN(CC1)CCN1CCC1=CC=C2C(=O)OCC2=C1 KTYDIPNIYXIARN-UHFFFAOYSA-N 0.000 description 1
- BHCSSFUUDZLJOV-UHFFFAOYSA-N 4-[[4-[2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]methyl]-3,4-dihydro-2h-chromene-7-carbonitrile Chemical compound C1COC2=CC(C#N)=CC=C2C1CN(CC1)CCN1CCC1=CC=C2C(=O)OCC2=C1C BHCSSFUUDZLJOV-UHFFFAOYSA-N 0.000 description 1
- UVVYFYLSZIMKMC-UHFFFAOYSA-N 4-bromo-2,3-dihydroinden-1-one Chemical compound BrC1=CC=CC2=C1CCC2=O UVVYFYLSZIMKMC-UHFFFAOYSA-N 0.000 description 1
- TZHQWUAOIWRFSW-UHFFFAOYSA-N 4-bromo-2,6-difluorobenzonitrile Chemical compound FC1=CC(Br)=CC(F)=C1C#N TZHQWUAOIWRFSW-UHFFFAOYSA-N 0.000 description 1
- RVCJOGNLYVNRDN-UHFFFAOYSA-N 4-bromo-2-methylbenzoic acid Chemical compound CC1=CC(Br)=CC=C1C(O)=O RVCJOGNLYVNRDN-UHFFFAOYSA-N 0.000 description 1
- LPEBMDFRIKYFCF-UHFFFAOYSA-N 4-bromo-2-methylbenzonitrile Chemical compound CC1=CC(Br)=CC=C1C#N LPEBMDFRIKYFCF-UHFFFAOYSA-N 0.000 description 1
- TWBFZKKJFREYES-UHFFFAOYSA-N 4-bromo-3-methoxybenzonitrile Chemical compound COC1=CC(C#N)=CC=C1Br TWBFZKKJFREYES-UHFFFAOYSA-N 0.000 description 1
- SKXUZFJOLNNWIG-UHFFFAOYSA-N 4-bromo-3-methylbenzonitrile Chemical compound CC1=CC(C#N)=CC=C1Br SKXUZFJOLNNWIG-UHFFFAOYSA-N 0.000 description 1
- VROAHIDWQHIBAY-UHFFFAOYSA-N 4-fluoro-2-methoxy-5-(2-oxoethyl)benzonitrile Chemical compound COC1=CC(F)=C(CC=O)C=C1C#N VROAHIDWQHIBAY-UHFFFAOYSA-N 0.000 description 1
- HGBKZVIQHCUHRI-UHFFFAOYSA-N 4-fluoro-2-methoxybenzonitrile Chemical compound COC1=CC(F)=CC=C1C#N HGBKZVIQHCUHRI-UHFFFAOYSA-N 0.000 description 1
- JGRHBNXLTLDACT-UHFFFAOYSA-N 4-fluoro-5-(2-hydroxyethyl)-2-methoxybenzonitrile Chemical compound COC1=CC(F)=C(CCO)C=C1C#N JGRHBNXLTLDACT-UHFFFAOYSA-N 0.000 description 1
- XPOIJNIQXJYQOV-UHFFFAOYSA-N 4-fluorobenzene-1,3-diol Chemical compound OC1=CC=C(F)C(O)=C1 XPOIJNIQXJYQOV-UHFFFAOYSA-N 0.000 description 1
- YDHFGFKBJLEKPP-UHFFFAOYSA-N 5-(2-piperazin-1-ylethyl)-2,1,3-benzoxadiazole;hydrochloride Chemical compound Cl.C1=CC2=NON=C2C=C1CCN1CCNCC1 YDHFGFKBJLEKPP-UHFFFAOYSA-N 0.000 description 1
- FYVIVKCNBZERBD-UHFFFAOYSA-N 5-[2-[4-(5,6,7,8-tetrahydrobenzo[f][2,1,3]benzoxadiazol-6-yl)piperazin-1-yl]ethyl]-3h-2-benzofuran-1-one Chemical compound C1CC2=CC3=NON=C3C=C2CC1N(CC1)CCN1CCC1=CC=C2C(=O)OCC2=C1 FYVIVKCNBZERBD-UHFFFAOYSA-N 0.000 description 1
- FNAVXRJXVHVMPA-UHFFFAOYSA-N 5-[2-[4-[6-(tetrazol-1-yl)-1,2,3,4-tetrahydronaphthalen-2-yl]piperazin-1-yl]ethyl]-2,1,3-benzoxadiazole Chemical compound C1=CC2=NON=C2C=C1CCN(CC1)CCN1C(CC1=CC=2)CCC1=CC=2N1C=NN=N1 FNAVXRJXVHVMPA-UHFFFAOYSA-N 0.000 description 1
- RWAVYCTUVYJSMU-UHFFFAOYSA-N 5-bromo-2,3-dihydro-1h-inden-2-amine Chemical compound C1=C(Br)C=C2CC(N)CC2=C1 RWAVYCTUVYJSMU-UHFFFAOYSA-N 0.000 description 1
- DDVQSZNNPLLKCW-UHFFFAOYSA-N 5-bromo-3,4-dihydro-1h-naphthalen-2-one Chemical compound C1C(=O)CCC2=C1C=CC=C2Br DDVQSZNNPLLKCW-UHFFFAOYSA-N 0.000 description 1
- JPKFRPZCKNFWIJ-UHFFFAOYSA-N 5-chloro-2,4-difluorobenzonitrile Chemical compound FC1=CC(F)=C(C#N)C=C1Cl JPKFRPZCKNFWIJ-UHFFFAOYSA-N 0.000 description 1
- AHBDGPJWXIMHOO-UHFFFAOYSA-N 5-chloro-2-fluoro-4-[2-[4-[2-(1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile Chemical compound C1=C(C#N)C(F)=CC(CCN2CCN(CCC=3C=C4COC(=O)C4=CC=3)CC2)=C1Cl AHBDGPJWXIMHOO-UHFFFAOYSA-N 0.000 description 1
- KHSKFYIKHSBBMV-UHFFFAOYSA-N 5-chloro-2-fluoro-4-[2-[4-[2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile Chemical compound CC1=C2COC(=O)C2=CC=C1CCN(CC1)CCN1CCC1=CC(F)=C(C#N)C=C1Cl KHSKFYIKHSBBMV-UHFFFAOYSA-N 0.000 description 1
- VSEBFWRYDORZJI-UHFFFAOYSA-N 5-nitro-1,3-dihydroinden-2-one Chemical compound [O-][N+](=O)C1=CC=C2CC(=O)CC2=C1 VSEBFWRYDORZJI-UHFFFAOYSA-N 0.000 description 1
- JARRBXVPQQXBGI-UHFFFAOYSA-N 5-nitroinden-2-one Chemical compound C1=C([N+](=O)[O-])C=CC2=CC(=O)C=C21 JARRBXVPQQXBGI-UHFFFAOYSA-N 0.000 description 1
- FGWRKZJKRYCDOF-UHFFFAOYSA-N 5-oxo-7,8-dihydro-6h-naphthalene-2-carbonitrile Chemical compound N#CC1=CC=C2C(=O)CCCC2=C1 FGWRKZJKRYCDOF-UHFFFAOYSA-N 0.000 description 1
- FGGBRDDEILDSDS-UHFFFAOYSA-N 6-[4-[2-(1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]-5,6,7,8-tetrahydronaphthalene-2-carbonitrile Chemical compound C1CC2=CC(C#N)=CC=C2CC1N(CC1)CCN1CCC1=CC=C2C(=O)OCC2=C1 FGGBRDDEILDSDS-UHFFFAOYSA-N 0.000 description 1
- PONGXMDLEGURRQ-UHFFFAOYSA-N 6-amino-5,6,7,8-tetrahydronaphthalene-2-carbonitrile Chemical compound N#CC1=CC=C2CC(N)CCC2=C1 PONGXMDLEGURRQ-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- DJQOOSBJCLSSEY-UHFFFAOYSA-N Acipimox Chemical compound CC1=CN=C(C(O)=O)C=[N+]1[O-] DJQOOSBJCLSSEY-UHFFFAOYSA-N 0.000 description 1
- FHHHOYXPRDYHEZ-COXVUDFISA-N Alacepril Chemical compound CC(=O)SC[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 FHHHOYXPRDYHEZ-COXVUDFISA-N 0.000 description 1
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 235000003911 Arachis Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 1
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 1
- 229910015845 BBr3 Inorganic materials 0.000 description 1
- 208000012904 Bartter disease Diseases 0.000 description 1
- 208000010062 Bartter syndrome Diseases 0.000 description 1
- XPCFTKFZXHTYIP-PMACEKPBSA-N Benazepril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N(CC(O)=O)C2=CC=CC=C2CC1)=O)CC1=CC=CC=C1 XPCFTKFZXHTYIP-PMACEKPBSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 229940123208 Biguanide Drugs 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 239000004072 C09CA03 - Valsartan Substances 0.000 description 1
- 239000002053 C09CA06 - Candesartan Substances 0.000 description 1
- GYJNSAGUYPZRRK-UHFFFAOYSA-N CC(C)(C)OC(=O)C(C(=O)OC)C1=C(Cl)C(F)=CC=C1C#N Chemical compound CC(C)(C)OC(=O)C(C(=O)OC)C1=C(Cl)C(F)=CC=C1C#N GYJNSAGUYPZRRK-UHFFFAOYSA-N 0.000 description 1
- DTPWZYSUQQHRKD-VIUAGAKSSA-N CC(O)=O.CC[C@H](C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@@H]1CSSC[C@H](NC(=O)[C@@H](N)CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1)[C@@H](C)O)C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O Chemical compound CC(O)=O.CC[C@H](C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@@H]1CSSC[C@H](NC(=O)[C@@H](N)CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1)[C@@H](C)O)C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O DTPWZYSUQQHRKD-VIUAGAKSSA-N 0.000 description 1
- 101150041968 CDC13 gene Proteins 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- IFYLTXNCFVRALQ-OALUTQOASA-N Ceronapril Chemical compound O([C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)P(O)(=O)CCCCC1=CC=CC=C1 IFYLTXNCFVRALQ-OALUTQOASA-N 0.000 description 1
- RKWGIWYCVPQPMF-UHFFFAOYSA-N Chloropropamide Chemical compound CCCNC(=O)NS(=O)(=O)C1=CC=C(Cl)C=C1 RKWGIWYCVPQPMF-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- TVZCRIROJQEVOT-CABCVRRESA-N Cromakalim Chemical compound N1([C@@H]2C3=CC(=CC=C3OC([C@H]2O)(C)C)C#N)CCCC1=O TVZCRIROJQEVOT-CABCVRRESA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 102000003779 Dipeptidyl-peptidases and tripeptidyl-peptidases Human genes 0.000 description 1
- 108090000194 Dipeptidyl-peptidases and tripeptidyl-peptidases Proteins 0.000 description 1
- 208000032928 Dyslipidaemia Diseases 0.000 description 1
- 108010063015 ES 1005 Proteins 0.000 description 1
- 108010078772 ES 8891 Proteins 0.000 description 1
- 108010061435 Enalapril Proteins 0.000 description 1
- 108010066671 Enalaprilat Proteins 0.000 description 1
- 229940118365 Endothelin receptor antagonist Drugs 0.000 description 1
- 241000854350 Enicospilus group Species 0.000 description 1
- HTQBXNHDCUEHJF-XWLPCZSASA-N Exenatide Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 HTQBXNHDCUEHJF-XWLPCZSASA-N 0.000 description 1
- 108010011459 Exenatide Proteins 0.000 description 1
- XQLWNAFCTODIRK-UHFFFAOYSA-N Gallopamil Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC(OC)=C(OC)C(OC)=C1 XQLWNAFCTODIRK-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- FAEKWTJYAYMJKF-QHCPKHFHSA-N GlucoNorm Chemical compound C1=C(C(O)=O)C(OCC)=CC(CC(=O)N[C@@H](CC(C)C)C=2C(=CC=CC=2)N2CCCCC2)=C1 FAEKWTJYAYMJKF-QHCPKHFHSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101001047038 Homo sapiens Inward rectifier potassium channel 13 Proteins 0.000 description 1
- 208000002682 Hyperkalemia Diseases 0.000 description 1
- 208000019025 Hypokalemia Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 102100022843 Inward rectifier potassium channel 13 Human genes 0.000 description 1
- 239000007760 Iscove's Modified Dulbecco's Medium Substances 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 229910013596 LiOH—H2O Inorganic materials 0.000 description 1
- 208000017170 Lipid metabolism disease Diseases 0.000 description 1
- 108010007859 Lisinopril Proteins 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 1
- IBAQFPQHRJAVAV-ULAWRXDQSA-N Miglitol Chemical compound OCCN1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO IBAQFPQHRJAVAV-ULAWRXDQSA-N 0.000 description 1
- ZFMITUMMTDLWHR-UHFFFAOYSA-N Minoxidil Chemical compound NC1=[N+]([O-])C(N)=CC(N2CCCCC2)=N1 ZFMITUMMTDLWHR-UHFFFAOYSA-N 0.000 description 1
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- SFQBTKJQLFIWBK-PFEQFJNWSA-N N#CC1=CC=C2CC(NC(=O)OC(C)(C)C)CCC2=C1.N#CC1=CC=C2C[C@H](NC(=O)OC(C)(C)C)CCC2=C1 Chemical compound N#CC1=CC=C2CC(NC(=O)OC(C)(C)C)CCC2=C1.N#CC1=CC=C2C[C@H](NC(=O)OC(C)(C)C)CCC2=C1 SFQBTKJQLFIWBK-PFEQFJNWSA-N 0.000 description 1
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 1
- 229910020889 NaBH3 Inorganic materials 0.000 description 1
- ZBBHBTPTTSWHBA-UHFFFAOYSA-N Nicardipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)CC=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZBBHBTPTTSWHBA-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 description 1
- XWURZHGKODQZMK-UHFFFAOYSA-N O.[Ru]=O Chemical compound O.[Ru]=O XWURZHGKODQZMK-UHFFFAOYSA-N 0.000 description 1
- 239000005480 Olmesartan Substances 0.000 description 1
- 229910002666 PdCl2 Inorganic materials 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- ZPHBZEQOLSRPAK-UHFFFAOYSA-N Phosphoramidon Natural products C=1NC2=CC=CC=C2C=1CC(C(O)=O)NC(=O)C(CC(C)C)NP(O)(=O)OC1OC(C)C(O)C(O)C1O ZPHBZEQOLSRPAK-UHFFFAOYSA-N 0.000 description 1
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 description 1
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 description 1
- 101100019728 Rattus norvegicus Kcnj1 gene Proteins 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 description 1
- 108010052164 Sodium Channels Proteins 0.000 description 1
- 102000018674 Sodium Channels Human genes 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- 102000003673 Symporters Human genes 0.000 description 1
- 108090000088 Symporters Proteins 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 229940123464 Thiazolidinedione Drugs 0.000 description 1
- 108010036928 Thiorphan Proteins 0.000 description 1
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 1
- VXFJYXUZANRPDJ-WTNASJBWSA-N Trandopril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@H]2CCCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 VXFJYXUZANRPDJ-WTNASJBWSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- LOJRLQRGBKTHDB-UHFFFAOYSA-M [Br-].[Zn+]CC1OCCO1 Chemical compound [Br-].[Zn+]CC1OCCO1 LOJRLQRGBKTHDB-UHFFFAOYSA-M 0.000 description 1
- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 description 1
- 238000002679 ablation Methods 0.000 description 1
- 229960002632 acarbose Drugs 0.000 description 1
- XUFXOAAUWZOOIT-UHFFFAOYSA-N acarviostatin I01 Natural products OC1C(O)C(NC2C(C(O)C(O)C(CO)=C2)O)C(C)OC1OC(C(C1O)O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O XUFXOAAUWZOOIT-UHFFFAOYSA-N 0.000 description 1
- NAHKRDFMCKGUAQ-UHFFFAOYSA-N acetic acid 2-(fluoromethyl)piperazine Chemical compound CC(O)=O.CC(O)=O.FCC1CNCCN1 NAHKRDFMCKGUAQ-UHFFFAOYSA-N 0.000 description 1
- DFDGRKNOFOJBAJ-UHFFFAOYSA-N acifran Chemical compound C=1C=CC=CC=1C1(C)OC(C(O)=O)=CC1=O DFDGRKNOFOJBAJ-UHFFFAOYSA-N 0.000 description 1
- 229950000146 acifran Drugs 0.000 description 1
- 229960003526 acipimox Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000001800 adrenalinergic effect Effects 0.000 description 1
- 239000000695 adrenergic alpha-agonist Substances 0.000 description 1
- 229950007884 alacepril Drugs 0.000 description 1
- 239000002170 aldosterone antagonist Substances 0.000 description 1
- 229940083712 aldosterone antagonist Drugs 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229960004601 aliskiren Drugs 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 239000003888 alpha glucosidase inhibitor Substances 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- CJCSPKMFHVPWAR-JTQLQIEISA-N alpha-methyl-L-dopa Chemical compound OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1 CJCSPKMFHVPWAR-JTQLQIEISA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- XSDQTOBWRPYKKA-UHFFFAOYSA-N amiloride Chemical compound NC(=N)NC(=O)C1=NC(Cl)=C(N)N=C1N XSDQTOBWRPYKKA-UHFFFAOYSA-N 0.000 description 1
- 229960002576 amiloride Drugs 0.000 description 1
- 229940093740 amino acid and derivative Drugs 0.000 description 1
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 description 1
- 229960000528 amlodipine Drugs 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 229940125364 angiotensin receptor blocker Drugs 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 238000005349 anion exchange Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000000879 anti-atherosclerotic effect Effects 0.000 description 1
- 239000000883 anti-obesity agent Substances 0.000 description 1
- 229940125708 antidiabetic agent Drugs 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 239000003524 antilipemic agent Substances 0.000 description 1
- 229940125710 antiobesity agent Drugs 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 150000001499 aryl bromides Chemical class 0.000 description 1
- 229960002274 atenolol Drugs 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 229960005370 atorvastatin Drugs 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- YEESUBCSWGVPCE-UHFFFAOYSA-N azanylidyneoxidanium iron(2+) pentacyanide Chemical compound [Fe++].[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.N#[O+] YEESUBCSWGVPCE-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 229960004530 benazepril Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 150000004283 biguanides Chemical class 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000012472 biological sample Substances 0.000 description 1
- 229960002781 bisoprolol Drugs 0.000 description 1
- VHYCDWMUTMEGQY-UHFFFAOYSA-N bisoprolol Chemical compound CC(C)NCC(O)COC1=CC=C(COCCOC(C)C)C=C1 VHYCDWMUTMEGQY-UHFFFAOYSA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- OZVBMTJYIDMWIL-AYFBDAFISA-N bromocriptine Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=C(Br)NC3=C1 OZVBMTJYIDMWIL-AYFBDAFISA-N 0.000 description 1
- 229960002802 bromocriptine Drugs 0.000 description 1
- LKXYJYDRLBPHRS-UHFFFAOYSA-N bromocyclopropane Chemical compound BrC1CC1 LKXYJYDRLBPHRS-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 229960000932 candesartan Drugs 0.000 description 1
- SGZAIDDFHDDFJU-UHFFFAOYSA-N candesartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SGZAIDDFHDDFJU-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229960000830 captopril Drugs 0.000 description 1
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- NPAKNKYSJIDKMW-UHFFFAOYSA-N carvedilol Chemical compound COC1=CC=CC=C1OCCNCC(O)COC1=CC=CC2=NC3=CC=C[CH]C3=C12 NPAKNKYSJIDKMW-UHFFFAOYSA-N 0.000 description 1
- 229960004195 carvedilol Drugs 0.000 description 1
- 238000005341 cation exchange Methods 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 229940083181 centrally acting adntiadrenergic agent methyldopa Drugs 0.000 description 1
- 229950005749 ceronapril Drugs 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 229960001761 chlorpropamide Drugs 0.000 description 1
- 230000001906 cholesterol absorption Effects 0.000 description 1
- 229960005025 cilazapril Drugs 0.000 description 1
- HHHKFGXWKKUNCY-FHWLQOOXSA-N cilazapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N2[C@@H](CCCN2CCC1)C(O)=O)=O)CC1=CC=CC=C1 HHHKFGXWKKUNCY-FHWLQOOXSA-N 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical class [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 229940097499 cozaar Drugs 0.000 description 1
- 229950004210 cromakalim Drugs 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229960005227 delapril Drugs 0.000 description 1
- WOUOLAUOZXOLJQ-MBSDFSHPSA-N delapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N(CC(O)=O)C1CC2=CC=CC=C2C1)CC1=CC=CC=C1 WOUOLAUOZXOLJQ-MBSDFSHPSA-N 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 229960004042 diazoxide Drugs 0.000 description 1
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 description 1
- 229960004166 diltiazem Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 229940029980 drug used in diabetes Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 229960000873 enalapril Drugs 0.000 description 1
- GBXSMTUPTTWBMN-XIRDDKMYSA-N enalapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 GBXSMTUPTTWBMN-XIRDDKMYSA-N 0.000 description 1
- 229960002680 enalaprilat Drugs 0.000 description 1
- MZYVOFLIPYDBGD-MLZQUWKJSA-N enalaprilat dihydrate Chemical compound O.O.C([C@H](N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 MZYVOFLIPYDBGD-MLZQUWKJSA-N 0.000 description 1
- 239000002308 endothelin receptor antagonist Substances 0.000 description 1
- 239000002792 enkephalinase inhibitor Substances 0.000 description 1
- 229960003133 ergot alkaloid Drugs 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- AWPMWZHWVKXADV-UHFFFAOYSA-N ethyl 2-(4-hydroxy-3-methoxyphenyl)acetate Chemical compound CCOC(=O)CC1=CC=C(O)C(OC)=C1 AWPMWZHWVKXADV-UHFFFAOYSA-N 0.000 description 1
- ALUSWBYRQYKJOR-UHFFFAOYSA-N ethyl 2-[3-methoxy-4-(trifluoromethylsulfonyloxy)phenyl]acetate Chemical compound CCOC(=O)CC1=CC=C(OS(=O)(=O)C(F)(F)F)C(OC)=C1 ALUSWBYRQYKJOR-UHFFFAOYSA-N 0.000 description 1
- NYDMLPORZQPRFL-UHFFFAOYSA-N ethyl 2-[6-(tetrazol-1-yl)pyridin-3-yl]acetate Chemical compound N1=CC(CC(=O)OCC)=CC=C1N1N=NN=C1 NYDMLPORZQPRFL-UHFFFAOYSA-N 0.000 description 1
- 229960001519 exenatide Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000013265 extended release Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical compound N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 229960002490 fosinopril Drugs 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 238000002825 functional assay Methods 0.000 description 1
- 230000009454 functional inhibition Effects 0.000 description 1
- 229960000457 gallopamil Drugs 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 229960004580 glibenclamide Drugs 0.000 description 1
- 229960004346 glimepiride Drugs 0.000 description 1
- WIGIZIANZCJQQY-RUCARUNLSA-N glimepiride Chemical compound O=C1C(CC)=C(C)CN1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)N[C@@H]2CC[C@@H](C)CC2)C=C1 WIGIZIANZCJQQY-RUCARUNLSA-N 0.000 description 1
- 229960001381 glipizide Drugs 0.000 description 1
- ZJJXGWJIGJFDTL-UHFFFAOYSA-N glipizide Chemical compound C1=NC(C)=CN=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZJJXGWJIGJFDTL-UHFFFAOYSA-N 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000013537 high throughput screening Methods 0.000 description 1
- 229960002474 hydralazine Drugs 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- CVVIJWRCGSYCMB-UHFFFAOYSA-N hydron;piperazine;dichloride Chemical compound Cl.Cl.C1CNCCN1 CVVIJWRCGSYCMB-UHFFFAOYSA-N 0.000 description 1
- 230000000396 hypokalemic effect Effects 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 229940090022 hyzaar Drugs 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 229960001195 imidapril Drugs 0.000 description 1
- KLZWOWYOHUKJIG-BPUTZDHNSA-N imidapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1C(N(C)C[C@H]1C(O)=O)=O)CC1=CC=CC=C1 KLZWOWYOHUKJIG-BPUTZDHNSA-N 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- UEXQBEVWFZKHNB-UHFFFAOYSA-N intermediate 29 Natural products C1=CC(N)=CC=C1NC1=NC=CC=N1 UEXQBEVWFZKHNB-UHFFFAOYSA-N 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229940103445 janumet Drugs 0.000 description 1
- 229940090473 januvia Drugs 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- NXFFJDQHYLNEJK-CYBMUJFWSA-N laropiprant Chemical compound C=1([C@@H](CC(O)=O)CCC=1C=1C=C(F)C=C(C2=1)S(=O)(=O)C)N2CC1=CC=C(Cl)C=C1 NXFFJDQHYLNEJK-CYBMUJFWSA-N 0.000 description 1
- 229950008292 laropiprant Drugs 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229960002394 lisinopril Drugs 0.000 description 1
- CZRQXSDBMCMPNJ-ZUIPZQNBSA-N lisinopril dihydrate Chemical compound O.O.C([C@H](N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 CZRQXSDBMCMPNJ-ZUIPZQNBSA-N 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000000210 loop of henle Anatomy 0.000 description 1
- UTEFBSAVJNEPTR-RGEXLXHISA-N loprazolam Chemical compound C1CN(C)CCN1\C=C/1C(=O)N2C3=CC=C([N+]([O-])=O)C=C3C(C=3C(=CC=CC=3)Cl)=NCC2=N\1 UTEFBSAVJNEPTR-RGEXLXHISA-N 0.000 description 1
- 229960003019 loprazolam Drugs 0.000 description 1
- 229960004773 losartan Drugs 0.000 description 1
- 229960004844 lovastatin Drugs 0.000 description 1
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 1
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004937 luminal membrane Anatomy 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 229950004994 meglitinide Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- OETHQSJEHLVLGH-UHFFFAOYSA-N metformin hydrochloride Chemical compound Cl.CN(C)C(=N)N=C(N)N OETHQSJEHLVLGH-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 1
- BTHMRXRBXYHLRA-FVGYRXGTSA-N methyl (2s)-2-amino-3-(4-nitrophenyl)propanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CC1=CC=C([N+]([O-])=O)C=C1 BTHMRXRBXYHLRA-FVGYRXGTSA-N 0.000 description 1
- XHICBJLJYKITQL-UHFFFAOYSA-N methyl 2-(3-bromo-4-cyanophenyl)acetate Chemical compound COC(=O)CC1=CC=C(C#N)C(Br)=C1 XHICBJLJYKITQL-UHFFFAOYSA-N 0.000 description 1
- WHOOJNWGGXXXII-UHFFFAOYSA-N methyl 2-(4-cyano-2-fluoro-5-methoxyphenyl)acetate Chemical compound COC(=O)CC1=CC(OC)=C(C#N)C=C1F WHOOJNWGGXXXII-UHFFFAOYSA-N 0.000 description 1
- DNONZNZKQUXXCM-UHFFFAOYSA-N methyl 2-(4-cyano-3-fluorophenyl)acetate Chemical compound COC(=O)CC1=CC=C(C#N)C(F)=C1 DNONZNZKQUXXCM-UHFFFAOYSA-N 0.000 description 1
- GYMTWFOUJTXQLN-UHFFFAOYSA-N methyl 2-[3-fluoro-4-(trifluoromethylsulfonyloxy)phenyl]acetate Chemical compound COC(=O)CC1=CC=C(OS(=O)(=O)C(F)(F)F)C(F)=C1 GYMTWFOUJTXQLN-UHFFFAOYSA-N 0.000 description 1
- OLRJFEVODYRLIY-UHFFFAOYSA-N methyl 2-[4-chloro-3-(trifluoromethoxy)phenyl]acetate Chemical compound COC(=O)CC1=CC=C(Cl)C(OC(F)(F)F)=C1 OLRJFEVODYRLIY-UHFFFAOYSA-N 0.000 description 1
- LFEGEWHLBLLABZ-UHFFFAOYSA-N methyl 2-piperazin-2-ylacetate Chemical compound COC(=O)CC1CNCCN1 LFEGEWHLBLLABZ-UHFFFAOYSA-N 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- 230000027939 micturition Effects 0.000 description 1
- 229960001110 miglitol Drugs 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 229960003632 minoxidil Drugs 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 229950006549 moveltipril Drugs 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical class C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
- 229960000698 nateglinide Drugs 0.000 description 1
- OELFLUMRDSZNSF-BRWVUGGUSA-N nateglinide Chemical compound C1C[C@@H](C(C)C)CC[C@@H]1C(=O)N[C@@H](C(O)=O)CC1=CC=CC=C1 OELFLUMRDSZNSF-BRWVUGGUSA-N 0.000 description 1
- 230000001452 natriuretic effect Effects 0.000 description 1
- 210000000885 nephron Anatomy 0.000 description 1
- 229960001783 nicardipine Drugs 0.000 description 1
- LBHIOVVIQHSOQN-UHFFFAOYSA-N nicorandil Chemical compound [O-][N+](=O)OCCNC(=O)C1=CC=CN=C1 LBHIOVVIQHSOQN-UHFFFAOYSA-N 0.000 description 1
- 229960002497 nicorandil Drugs 0.000 description 1
- 229960001597 nifedipine Drugs 0.000 description 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
- VZWXXKDFACOXNT-UHFFFAOYSA-N niludipine Chemical compound CCCOCCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCOCCC)C1C1=CC=CC([N+]([O-])=O)=C1 VZWXXKDFACOXNT-UHFFFAOYSA-N 0.000 description 1
- 229950000109 niludipine Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229940074355 nitric acid Drugs 0.000 description 1
- 229960002460 nitroprusside Drugs 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- VTRAEEWXHOVJFV-UHFFFAOYSA-N olmesartan Chemical compound CCCC1=NC(C(C)(C)O)=C(C(O)=O)N1CC1=CC=C(C=2C(=CC=CC=2)C=2NN=NN=2)C=C1 VTRAEEWXHOVJFV-UHFFFAOYSA-N 0.000 description 1
- 229960005117 olmesartan Drugs 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000004031 partial agonist Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- FAXGPCHRFPCXOO-LXTPJMTPSA-N pepstatin A Chemical class OC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)NC(=O)CC(C)C FAXGPCHRFPCXOO-LXTPJMTPSA-N 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 125000001151 peptidyl group Chemical group 0.000 description 1
- 238000003359 percent control normalization Methods 0.000 description 1
- 229960002582 perindopril Drugs 0.000 description 1
- IPVQLZZIHOAWMC-QXKUPLGCSA-N perindopril Chemical compound C1CCC[C@H]2C[C@@H](C(O)=O)N(C(=O)[C@H](C)N[C@@H](CCC)C(=O)OCC)[C@H]21 IPVQLZZIHOAWMC-QXKUPLGCSA-N 0.000 description 1
- 239000000810 peripheral vasodilating agent Substances 0.000 description 1
- 229960002116 peripheral vasodilator Drugs 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- BWSDNRQVTFZQQD-AYVHNPTNSA-N phosphoramidon Chemical compound O([P@@](O)(=O)N[C@H](CC(C)C)C(=O)N[C@H](CC=1[C]2C=CC=CC2=NC=1)C(O)=O)[C@H]1O[C@@H](C)[C@H](O)[C@@H](O)[C@@H]1O BWSDNRQVTFZQQD-AYVHNPTNSA-N 0.000 description 1
- 108010072906 phosphoramidon Proteins 0.000 description 1
- 229960004838 phosphoric acid Drugs 0.000 description 1
- 229960002310 pinacidil Drugs 0.000 description 1
- 229960005095 pioglitazone Drugs 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 229960002797 pitavastatin Drugs 0.000 description 1
- VGYFMXBACGZSIL-MCBHFWOFSA-N pitavastatin Chemical compound OC(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 VGYFMXBACGZSIL-MCBHFWOFSA-N 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000004036 potassium channel stimulating agent Substances 0.000 description 1
- 208000024896 potassium deficiency disease Diseases 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 108010029667 pramlintide Proteins 0.000 description 1
- 229960004457 pramlintide acetate Drugs 0.000 description 1
- 229960002965 pravastatin Drugs 0.000 description 1
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 1
- IENZQIKPVFGBNW-UHFFFAOYSA-N prazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 IENZQIKPVFGBNW-UHFFFAOYSA-N 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- 238000002810 primary assay Methods 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- UZQBKCWYZBHBOW-UHFFFAOYSA-N propan-2-yl 4-cyclohexyl-2-hydroxy-3-[[3-methylsulfanyl-2-[[2-(morpholine-4-carbonylamino)-3-phenylpropanoyl]amino]propanoyl]amino]butanoate Chemical compound C1CCCCC1CC(C(O)C(=O)OC(C)C)NC(=O)C(CSC)NC(=O)C(NC(=O)N1CCOCC1)CC1=CC=CC=C1 UZQBKCWYZBHBOW-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 229960003712 propranolol Drugs 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 229960001455 quinapril Drugs 0.000 description 1
- JSDRRTOADPPCHY-HSQYWUDLSA-N quinapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CC2=CC=CC=C2C1)C(O)=O)CC1=CC=CC=C1 JSDRRTOADPPCHY-HSQYWUDLSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 229960003401 ramipril Drugs 0.000 description 1
- HDACQVRGBOVJII-JBDAPHQKSA-N ramipril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@@H]2CCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 HDACQVRGBOVJII-JBDAPHQKSA-N 0.000 description 1
- 238000009790 rate-determining step (RDS) Methods 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229960002354 repaglinide Drugs 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 229960004586 rosiglitazone Drugs 0.000 description 1
- 229960000672 rosuvastatin Drugs 0.000 description 1
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- QGJUIPDUBHWZPV-SGTAVMJGSA-N saxagliptin Chemical compound C1C(C2)CC(C3)CC2(O)CC13[C@H](N)C(=O)N1[C@H](C#N)C[C@@H]2C[C@@H]21 QGJUIPDUBHWZPV-SGTAVMJGSA-N 0.000 description 1
- 108010033693 saxagliptin Proteins 0.000 description 1
- 229960004937 saxagliptin Drugs 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000001235 sensitizing effect Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 229960002855 simvastatin Drugs 0.000 description 1
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 1
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229960002909 spirapril Drugs 0.000 description 1
- HRWCVUIFMSZDJS-SZMVWBNQSA-N spirapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CC2(C1)SCCS2)C(O)=O)CC1=CC=CC=C1 HRWCVUIFMSZDJS-SZMVWBNQSA-N 0.000 description 1
- 108700035424 spirapril Proteins 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid Chemical compound NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 229940032330 sulfuric acid Drugs 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000000948 sympatholitic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 229960004084 temocapril Drugs 0.000 description 1
- FIQOFIRCTOWDOW-BJLQDIEVSA-N temocapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N(CC(O)=O)C[C@H](SC1)C=1SC=CC=1)=O)CC1=CC=CC=C1 FIQOFIRCTOWDOW-BJLQDIEVSA-N 0.000 description 1
- 108010069247 terlakiren Proteins 0.000 description 1
- RBLOMFQUEUBEBG-UHFFFAOYSA-N tert-butyl 2,5-diazabicyclo[2.2.2]octane-2-carboxylate Chemical compound C1CC2N(C(=O)OC(C)(C)C)CC1NC2 RBLOMFQUEUBEBG-UHFFFAOYSA-N 0.000 description 1
- FMLPQHJYUZTHQS-UHFFFAOYSA-N tert-butyl 3-methylpiperazine-1-carboxylate Chemical compound CC1CN(C(=O)OC(C)(C)C)CCN1 FMLPQHJYUZTHQS-UHFFFAOYSA-N 0.000 description 1
- WQJIAVKZNGOREL-UHFFFAOYSA-N tert-butyl 4-(5,6,7,8-tetrahydrobenzo[f][2,1,3]benzoxadiazol-6-yl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1CC2=CC3=NON=C3C=C2CC1 WQJIAVKZNGOREL-UHFFFAOYSA-N 0.000 description 1
- RWWHKNKMZGVQCD-UHFFFAOYSA-N tert-butyl 4-(5-nitro-2,3-dihydro-1h-inden-2-yl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1CC2=CC([N+]([O-])=O)=CC=C2C1 RWWHKNKMZGVQCD-UHFFFAOYSA-N 0.000 description 1
- GPFMBVLQTQMYGW-INIZCTEOSA-N tert-butyl 4-[(2S)-1-methoxy-3-(4-nitrophenyl)-1-oxopropan-2-yl]piperazine-1-carboxylate Chemical compound COC([C@H](CC1=CC=C(C=C1)[N+](=O)[O-])N1CCN(CC1)C(=O)OC(C)(C)C)=O GPFMBVLQTQMYGW-INIZCTEOSA-N 0.000 description 1
- KQRQBVURQOSBJG-SFHVURJKSA-N tert-butyl 4-[(2s)-6-cyano-1,2,3,4-tetrahydronaphthalen-2-yl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1[C@@H]1CC2=CC=C(C#N)C=C2CC1 KQRQBVURQOSBJG-SFHVURJKSA-N 0.000 description 1
- JBMHCZFPJWQCNQ-UHFFFAOYSA-N tert-butyl 4-[7-(1,3-dioxoisoindol-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1CC2=CC(N3C(C4=CC=CC=C4C3=O)=O)=CC=C2CC1 JBMHCZFPJWQCNQ-UHFFFAOYSA-N 0.000 description 1
- YIUGMVHOHIXRJH-CQSZACIVSA-N tert-butyl N-[(2R)-6-cyano-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate Chemical compound N#CC1=CC=C2C[C@H](NC(=O)OC(C)(C)C)CCC2=C1 YIUGMVHOHIXRJH-CQSZACIVSA-N 0.000 description 1
- YIUGMVHOHIXRJH-UHFFFAOYSA-N tert-butyl n-(6-cyano-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate Chemical compound N#CC1=CC=C2CC(NC(=O)OC(C)(C)C)CCC2=C1 YIUGMVHOHIXRJH-UHFFFAOYSA-N 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
- LJJKNPQAGWVLDQ-SNVBAGLBSA-N thiorphan Chemical compound OC(=O)CNC(=O)[C@@H](CS)CC1=CC=CC=C1 LJJKNPQAGWVLDQ-SNVBAGLBSA-N 0.000 description 1
- 229960002277 tolazamide Drugs 0.000 description 1
- OUDSBRTVNLOZBN-UHFFFAOYSA-N tolazamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1CCCCCC1 OUDSBRTVNLOZBN-UHFFFAOYSA-N 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
- 229960002051 trandolapril Drugs 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical class [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229960004699 valsartan Drugs 0.000 description 1
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 238000002424 x-ray crystallography Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/76—Nitrogen atoms to which a second hetero atom is attached
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/04—1,2,3-Oxadiazoles; Hydrogenated 1,2,3-oxadiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/12—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/06—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
- C07D295/073—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
- C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/30—Oxygen atoms, e.g. delta-lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
Definitions
- ROMK Renal Outer Medullary Potassium channel
- Kirl.l The Renal Outer Medullary Potassium (ROMK) channel (Kirl.l) (see e.g., Ho, K., et al., Cloning and expression of an inwardly rectifying ATP-regulated potassium channel, Nature, 1993, 362(6415): p. 31-8.1, 2 ; and Shuck, M.E., et al., Cloning and characterization of multiple forms of the human kidney ROM-K potassium channel, J Biol Chem, 1994, 269(39): p.
- ROMK Renal Outer Medullary Potassium
- TALH thick ascending loop of Henle
- CCD cortical collecting duct
- ROMK provides a pathway for potassium secretion that is tightly coupled to sodium uptake through the amiloride-sensitive sodium channel (see Reinalter, S.C., et al., Pharmacotyping of hypokalaemic salt-losing tubular disorders, Acta Physiol Scand, 2004, 181(4): p. 513-21 ; and Wang, W., Renal potassium channels: recent developments, Curr Opin Nephrol Hypertens, 2004, 13(5): p. 549-55 ).
- ROMK channel also referred to herein as inhibitors of ROMK or ROMK inhibitors
- ROMK channel are predicted to represent novel diuretics for the treatment of hypertension and other conditions where treatment with a diuretic would be beneficial with potentially reduced liabilities (i.e., hypo- or hyperkalemia, new onset of diabetes, dyslipidemia) over the currently used clinical agents (see Lifton, R.P., A.G. Gharavi, and D.S. Geller, Molecular mechanisms of human hypertension, Cell, 2001, 104(4): p. 545-56 ).
- Human genetics Ji, W., et al., Rare independent mutations in renal salt handling genes contribute to blood pressure variation, Nat Genet, 2008, 40(5): p.
- the present invention provides compounds of Formula I and the pharmaceutically acceptable salts thereof.
- the compounds of Formula I are inhibitors of the ROMK (Kir1.1) channel and can thus act as diuretics and natriuretics and are valuable pharmaceutically active compounds for the therapy and prophylaxis of diseases, including, but not limited to, cardiovascular diseases such as hypertension and conditions resulting from excessive salt and water retention.
- Methods of treatment comprising administering a therapeutically or prophylactically effective amount of a compound of Formula I to a patient in need of a diuretic and/or natriuretic agent are also provided.
- Compounds of Formula I can be used in combination with other therapeutically effective agents, including other drugs useful for the treatment of hypertension and conditions resulting from excessive salt and water retention.
- the invention furthermore relates to processes for preparing compounds of Formula I, and pharmaceutical compositions which comprise compounds of Formula I. s
- Z 1 is selected from the group consisting of:
- Z 2 is selected from the group consisting of: one of W 1 and W 2 is N and the other is CH;
- R 1 and R 2 are each independently selected from the group consisting of -H, -F, -Cl, -Br, -C 3 -C 6 cycloalkyl, -OR 8 , -SR 8 , -SOR 8 , -SO
- Z 2 is selected from the group consisting of: X and X 1 are each independently selected from -H and -C 1-6 alkyl; Y and Y 1 are each independently selected from -H and -C 1-6 alkyl, or Y 1 is joined together with Z 2 and the carbon to which both are attached to form a fused ring system selected from the group consisting of: R 5 is selected from -H, -CH 3 , -C 1-6 alkyl and -C(O)OC 1-3 alkyl; and R 6 is selected from -H, -CH 3 , -C 1-6 alkyl and -C(O)OC 1-3 alkyl, or R 6 is joined together with Z 2 and the intervening carbons to which each is attached to form a fused ring system selected from: and all other variables are as defined in Formula I .
- Embodiment A are compounds of Formula I or II and the pharmaceutically acceptable salts thereof wherein Z 1 is selected from:
- Z 2 is selected from the group consisting of:
- R 2 is -H or -CH 3 ; and R d is -H.
- Embodiment B are compounds of Formula I or II and the pharmaceutically acceptable salts thereof wherein Z 1 is
- Z 2 is selected from the group consisting of: and (2) compounds wherein R 6 is joined with Z 2 to form the fused ring system and R 4a is -NO 2 or -CN.
- R 4a is -NO 2 or -CN.
- Embodiment C are compounds of Formula I or II and the pharmaceutically acceptable salts thereof wherein Z 1 is wherein one of R 3a and R 3b is -CN and the other is selected from -F, -Cl, -OCH 3 , and -OCH 2 CH 3 .
- Embodiment D are compounds of Formula I or II and the pharmaceutically acceptable salts thereof wherein Z 1 is In a class of Embodiment D are compounds wherein (1) Z 2 is or (2) R 6 is joined with Z 2 to form the fused ring system
- R 3a and R 4a are independently selected from the group consisting of -CN and -NO 2
- R 3b and R 4b is are independently selected from the group consisting of -H, -F, -Cl, -Br, -CH 3 , -S-CH 3 , -NH-CH 3 , -O-cyclopropyl and -OC 1-3 alkyl optionally substituted with 1-3 of -F.
- R 3a is -NO 2 then R 3b and R a are both -H.
- R a and R b are each independently selected from the group consisting of -H, -F, -Cl, -CH 3 optionally substituted with 1 to 3 of -F, and -OCH 3 optionally substituted with 1 to 3 of -F; and more particularly -H, -F, and -CH 3 .
- R c and R d are each independently selected from the group consisting of -H, -F, -Cl, -CH 3 optionally substituted with 1 to 3 of -F, and -OCH 3 optionally substituted with 1 to 3 of -F; and more particularly -H, -F, and -CH 3 .
- alkyl is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Commonly used abbreviations for alkyl groups are used throughout the specification.
- Cycloalkyl is a cyclized alkyl ring having the indicated number of carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cycloalkyl ring may be substituted on any available carbon which results in the creation of a stable structure, including the ring carbon which serves as the point of attachment to the rest of the molecule.
- an alkyl group that can be optionally substituted with 1-3 of -F includes, but is not limited to, -CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 3 , -CH 2 -CH 2 F -CH 2 -CHF 2 , -CHF-CH 2 F, -CH 2 CF 3 , -CHF-CHF 2 , -(CH 2 ) 2 CH 3 , -CH(CF 3 )-CH 3 , -(CH 2 ) 3 -CF 3 , -(CH 2 ) 5 -CF 3 , as appropriate for the defined number of carbon atoms for the given alkyl group.
- Halo or halogen refers to -F (fluoro), -Cl (chloro), -Br (bromo) and -I (iodo).
- Preferred halogens are -F and -Cl.
- variables depicted in a structural formula with a "floating" bond such as each of substituents R a , R b , R c , R d , Re and Rf in structural Formulas I and II, are permitted on any available carbon atom in the ring to which each is attached.
- the present invention encompasses all stereoisomeric forms of the compounds of Formula I. Centers of asymmetry that are present in the compounds of Formula I can all independently of one another have (R) configuration or (S) configuration. When bonds to the chiral carbon are depicted as straight lines in the structural Formulas of the invention, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the Formula. Similarly, when a compound name is recited without a chiral designation for a chiral carbon, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence individual enantiomers and mixtures thereof, are embraced by the name. The production of specific stereoisomers or mixtures thereof may be identified in the Examples where such stereoisomers or mixtures were obtained, but this in no way limits the inclusion of all stereoisomers and mixtures thereof from being within the scope of this invention.
- the invention includes all possible enantiomers and diastereomers and mixtures of two or more stereoisomers, for example mixtures of enantiomers and/or diastereomers, in all ratios.
- enantiomers are a subject of the invention in enantiomerically pure form, both as levorotatory and as dextrorotatory antipodes, in the form of racemates and in the form of mixtures of the two enantiomers in all ratios.
- the invention includes both the cis form and the trans form as well as mixtures of these forms in all ratios.
- the preparation of individual stereoisomers can be carried out, if desired, by separation of a mixture by customary methods, for example by chromatography or crystallization, by the use of stereochemically uniform starting materials for the synthesis or by stereoselective synthesis.
- a derivatization can be carried out before a separation of stereoisomers.
- the separation of a mixture of stereoisomers can be carried out at an intermediate step during the synthesis of a compound of Formula I or it can be done on a final racemic product.
- Absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing a stereogenic center of known configuration.
- the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
- the present invention is meant to include all suitable isotopic variations of the compounds of Formula I.
- different isotopic forms of hydrogen (H) include protium ( 1 H) and deuterium ( 2 H).
- Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
- Isotopically-enriched compounds within Formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
- the invention also includes the corresponding physiologically or toxicologically acceptable salts, in particular the pharmaceutically utilizable salts.
- the compounds of Formula I which contain acidic groups can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts or as ammonium salts.
- such salts include but are not limited to sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids.
- Compounds of Formula I which contain one or more basic groups i.e.
- the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). Salts can be obtained from the compounds of Formula I by customary methods which are known to the person skilled in the art, for example by combination with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange from other salts.
- the present invention also includes all salts of the compounds of Formula I which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of physiologically (i.e., pharmaceutically) acceptable salts.
- compounds of the present invention may exist in amorphous form and/or one or more crystalline forms, and as such all amorphous and crystalline forms and mixtures thereof of the compounds of Formula I are intended to be included within the scope of the present invention.
- some of the compounds of the instant invention may form solvates with water (i.e., a hydrate) or common organic solvents.
- solvates and hydrates, particularly the pharmaceutically acceptable solvates and hydrates, of the instant compounds are likewise encompassed within the scope of this invention, along with un-solvated and anhydrous forms.
- esters can optionally be made by esterification of an available carboxylic acid group or by formation of an ester on an available hydroxy group in a compound.
- labile amides can be made.
- Pharmaceutically acceptable esters or amides of the compounds of this invention may be prepared to act as pro-drugs which can be hydrolyzed back to an acid (or -COO- depending on the pH of the fluid or tissue where conversion takes place) or hydroxy form particularly in vivo and as such are encompassed within the scope of this invention.
- Examples of pharmaceutically acceptable pro-drug modifications include, but are not limited to, -C 1-6 alkyl esters and -C 1-6 alkyl substituted with phenyl esters.
- the compounds within the generic structural formulas, embodiments and specific compounds described and claimed herein encompass salts, all possible stereoisomers and tautomers, physical forms (e.g., amorphous and crystalline forms), solvate and hydrate forms thereof and any combination of these forms, as well as the salts thereof, pro-drug forms thereof, and salts of pro-drug forms thereof, where such forms are possible unless specified otherwise.
- an object of the instant invention is to provide a method for inhibiting ROMK comprising administering a compound of Formula I in a ROMK-inhibitory effective amount to a patient in need thereof.
- the inhibition of ROMK by the compounds of Formula I can be examined, for example, in any of the activity assays described below.
- Another object is to provide a method for causing diuresis, natriuresis or both, comprising administering a compound of Formula I in a therapeutically effective amount to a patient in need thereof.
- this invention further provides the use of compounds of Formula I in methods for treatment of, prevention of or reduction of risk for developing medical conditions that benefit from increased excretion of water and sodium, such as but not limited to one or more of hypertension, heart failure (both acute and chronic, also known as congestive heart failure) and/or other conditions resulting from excessive salt and water retention.
- pulmonary arterial hypertension PAH
- cardiovascular disease diabetes, endothelial dysfunction, diastolic dysfunction, stable and unstable angina pectoris, thromboses, restenosis, myocardial infarction, stroke, cardiac insufficiency, pulmonary hypertonia, atherosclerosis, hepatic cirrhosis, ascitis, pre-eclampsia, cerebral edema, nephropathy, nephrotic syndrome, acute and chronic kidney insufficiency, hypercalcemia, Dent's disease, Meniere's disease, edetamous states, and other conditions for which a diuretic would have therapeutic or prophylactic benefit.
- the compounds of the invention can be administered to a patient having, or at risk of having, one or more conditions for which a diuretic would have therapeutic or prophylactic benefit such as those described herein.
- compounds that are ROMK inhibitors can be identified as those compounds which, when tested, have an IC 50 of 5 ⁇ M or less, preferably 1 ⁇ M or less, and more preferably 0.25 ⁇ M or less, in at least one of the following assays: 1) the 86 Rb + Efflux Assay and 2) the Thallium Flux Assay. These assays are described in more detail further below.
- the dosage amount of the compound to be administered depends on the individual case and is, as is customary, to be adapted to the individual circumstances to achieve an optimum effect. Thus, it depends on the nature and the severity of the disorder to be treated, and also on the sex, age, weight and individual responsiveness of the human or animal to be treated, on the efficacy and duration of action of the compounds used, on whether the therapy is acute or chronic or prophylactic, or on whether other active compounds are administered in addition to compounds of Formula I. A consideration of these factors is well within the purview of the ordinarily skilled clinician for the purpose of determining the therapeutically effective or prophylactically effective dosage amount needed to prevent, counter, or arrest the progress of the condition. It is expected that the compound will be administered chronically on a daily basis for a length of time appropriate to treat or prevent the medical condition relevant to the patient, including a course of therapy lasting days, months, years or the life of the patient.
- a daily dose of approximately 0.001 to 100 mg/kg, preferably 0.001 to 30 mg/kg, in particular 0.001 to 10 mg/kg (in each case mg per kg of bodyweight) is appropriate for administration to an adult weighing approximately 75 kg in order to obtain the desired results.
- the daily dose is preferably administered in a single dose or, in particular when larger amounts are administered, can be divided into several, for example two, three or four individual doses, and may be, for example but not limited to, 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 75 mg, 100 mg, etc., on a daily basis. In some cases, depending on the individual response, it may be necessary to deviate upwards or downwards from the given daily dose.
- the compound may be formulated for immediate or modified release such as extended or controlled release.
- patient includes animals, preferably mammals and especially humans, who use the instant active agents for the prohhylaxis or treatment of a medical condition.
- Administering of the drug to the patient includes both self-administration and administration to the patient by another person.
- the patient may be in need of treatment for an existing disease or medical condition, or may desire prophylactic treatment to prevent or reduce the risk for developing said disease or medical condition or developing long-term complications from a disease or medical condition.
- therapeutically effective amount is intended to mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, a system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
- a prophylactically effective amount is intended to mean that amount of a pharmaceutical drug that will prevent or reduce the risk of occurrence of the biological or medical event that is sought to be prevented in a tissue, a system, animal or human by a researcher, veterinarian, medical doctor or other clinician.
- a specific daily dosage amount can simultaneously be both a therapeutically effective amount, e.g., for treatment of hypertension, and a prophylactically effective amount, e.g., for prevention or reduction of risk of myocardial infarction or prevention and reduction of risk for complications related to hypertension.
- the ROMK inhibitors may be administered via any suitable route of administration such as, for example, orally, parenterally, or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
- parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. Oral formulations are preferred, particularly solid oral dosage units such as pills, tablets or capsules.
- compositions comprised of a compound of Formula I and a pharmaceutically acceptable carrier.
- the pharmaceutical compositions of this invention containing the active ingredient may be in forms such as pills, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
- Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
- Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients, which are suitable for the manufacture of tablets.
- excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, mannitol, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc.
- compositions may also contain other customary additives, for example, wetting agents, stabilizers, emulsifiers, dispersants, preservatives, sweeteners, colorants, flavorings, aromatizers, thickeners, diluents, buffer substances, solvents, solubilizers, agents for achieving a depot effect, salts for altering the osmotic pressure, coating agents or antioxidants.
- customary additives for example, wetting agents, stabilizers, emulsifiers, dispersants, preservatives, sweeteners, colorants, flavorings, aromatizers, thickeners, diluents, buffer substances, solvents, solubilizers, agents for achieving a depot effect, salts for altering the osmotic pressure, coating agents or antioxidants.
- Oral immediate-release and time-controlled release dosage forms may be employed, as well as enterically coated oral dosage forms. Tablets may be uncoated or they may be coated by known techniques for aesthetic purposes, to mask taste or for other reasons. Coatings can also be used to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
- Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients is mixed with water or miscible solvents such as propylene glycol, PEGs and ethanol, or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
- an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
- water or miscible solvents such as propylene glycol, PEGs and ethanol
- an oil medium for example peanut oil, liquid paraffin, or olive oil.
- Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
- Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
- the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
- Sweetening agents and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
- Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose.
- the instant invention also encompasses a process for preparing a pharmaceutical composition comprising combining a compound of Formula I with a pharmaceutically acceptable carrier. Also encompassed is the pharmaceutical composition which is made by combining a compound of Formula I with a pharmaceutically acceptable carrier.
- the carrier is comprised of one or more pharmaceutically acceptable excipients.
- a therapeutically effective amount of a compound of this invention can be used for the preparation of a medicament useful for inhibiting ROMK, for causing diuresis and/or natriuresis, and/or for treating, preventing or reducing the risk for any of the medical conditions described herein, in dosage amounts described herein.
- the amount of active compound of Formula I and/or its pharmaceutically acceptable salts in the pharmaceutical composition may be, for example but not limited to, from 0.1 to 200 mg, preferably from 0.1 to 50 mg, per dose on a free acid/free base weight basis, but depending on the type of the pharmaceutical composition and potency of the active ingredient it could also be lower or higher.
- Pharmaceutical compositions usually comprise 0.5 to 90 percent by weight of the active compound on a free acid/free base weight basis.
- the compounds of Formula I inhibit ROMK.
- They can also be employed as a scientific tool or as aid for biochemical investigations in which such an effect on ROMK is intended, and also for diagnostic purposes, for example in the in vitro diagnosis of cell samples or tissue samples.
- the compounds of Formula I can also be employed as intermediates for the preparation of other pharmaceutically active compounds.
- One or more additional pharmacologically active agents may be administered in combination with a compound of Formula I.
- An additional active agent (or agents) is intended to mean a pharmaceutically active agent (or agents) different from the compound of Formula I.
- any suitable additional active agent or agents including but not limited to antihypertensive agents, anti-atherosclerotic agents such as a lipid modifying compound, antidiabetic agents and/or anti-obesity agents may be used in any combination with the compound of Formula I in a single dosage formulation (a fixed dose drug combination), or may be administered to the patient in one or more separate dosage formulations which allows for concurrent or sequential administration of the active agents (co-administration of the separate active agents).
- angiotensin converting enzyme inhibitors e.g, alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, moveltipril, perindopril, quinapril, ramipril, spirapril, temocapril, or trandolapril), angiotensin II receptor antagonists also known as angiotensis receptor blockers or ARBs (e.g., losartan i.e., COZAAR®, valsartan, candesartan, olmesartan, telmesartan and any of these drugs used in combination with hydrochlorothiazide such as HYZAAR®), neutral endopeptidase inhibitors (e.g., alacepril, benazepril
- urea derivatives of di- and tripeptides See U.S. Pat. No. 5,116,835 ), amino acids and derivatives ( U.S. Patents 5,095,119 and 5,104,869 ), amino acid chains linked by non-peptidic bonds ( U.S. Patent 5,114,937 ), di- and tripeptide derivatives ( U.S. Patent 5,106,835 ), peptidyl amino diols ( U.S. Patents 5,063,208 and 4,845,079 ) and peptidyl beta-aminoacyl aminodiol carbamates ( U.S. Patent 5,089,471 ); also, a variety of other peptide analogs as disclosed in the following U.S.
- Patent 4,980,283 and fluoro- and chloro-derivatives of statone-containing peptides ( U.S. Patent 5,066,643 ), enalkrein, RO 42-5892, A 65317, CP 80794, ES 1005, ES 8891, SQ 34017, aliskiren (2(S),4(S),5(S),7(S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)-phenyl]-octanamid hemifumarate) SPP600, SPP630 and SPP635), endothelin receptor antagonists, vasodilators (e.g.
- calcium channel blockers e.g., amlodipine, nifedipine, verastrial, diltiazem, gallopamil, niludipine, nimodipins, nicardipine
- potassium channel activators e.g., nicorandil, pinacidil, cromakalim, minoxidil, aprilkalim, loprazolam
- diuretics e.g., hydrochlorothiazide
- sympatholitics e.g., beta-adrenergic blocking drugs (e.g., propranolol, atenolol, bisoprolol, carvedilol, metoprolol, or metoprolol tartate), alpha adrenergic blocking drugs (e.g., doxazocin, prazocin or alpha methyldopa) central alpha adrenergic agonists, peripheral vasodilators (e.
- lipid lowering agents e.g., HMG-CoA reductase inhibitors such as simvastatin, lovastatin, pravastatin, atorvastatin, pitavastatin and rosuvastatin, and cholesterol absorption inhibitors such as ezetimibe
- HMG-CoA reductase inhibitors such as simvastatin, lovastatin, pravastatin, atorvastatin, pitavastatin and rosuvastatin, and cholesterol absorption inhibitors such as ezetimibe
- niacin in immediate-release or controlled release forms and particularly niacin in combination with a DP antagonist such as laropiprant (TREDAPTIVE ® ) and/or with an HMG-CoA reductase inhibitor
- niacin receptor agonists such as acipimox and acifran, as well as niacin receptor partial agonists
- metabolic altering agents including insulin sensitizing agents and related compounds for
- synthesis of the covered compounds starts with alkylation of electrophile 1-1 (such as bromide, iodide, mesylatem or tosylate) with N-Boc protected piperazine ( 1-2 ) under basic conditions.
- the Boc protecting group Greene, T.; Wuts, P. G. M. protective Groups in Organic Synthesis, John Wiley and Sons, Inc., New York, NY 1991
- the resulting piperazine 1-4 was alkylated for a second time with the corresponding electrophile (E) 1-5 to yield the product 1-6 .
- the alkylation can be achieved under reductive amination conditions with the corresponding aldehyde or ketone using NaCNCH 3 or Na(OAc) 3 BH ( Scheme 2 ).
- Some compounds were made via a combination of the two alkylation methods, depending on whether the electrophile or aldehyde (ketone) is more easily accessible.
- the final product may be prepared in one single step via a double alkylation or reductive amination with piperazine 3-1 (Scheme 3).
- intermediate 1-3 can also be prepared via a one pot ozonolysis - reductive amination method, when amine 4-1 is more easily accessible ( Scheme 4 ).
- tert- butyl diallylcarbamate 4-2 was first treated under ozonolysis conditions, which was followed by addition of amine 4-1 , triethylamine, and Na(OAc) 3 BH. Further stirring of the reaction gave rise to intermediate 1-3 . Removal of the Boc group gave rise to 1-4 , which was further alkylated to furnish the final compound.
- reactions sensitive to moisture or air were performed under nitrogen or argon using anhydrous solvents and reagents.
- the progress of reactions was determined by either analytical thin layer chromatography (TLC) usually performed with E. Merck precoated TLC plates, silica gel 60F-254, layer thickness 0.25 mm or liquid chromatography-mass spectrometry (LC-MS).
- TLC analytical thin layer chromatography
- LC-MS liquid chromatography-mass spectrometry
- the analytical LC-MS system used consisted of a Waters ZQ platform with electrospray ionization in positive ion detection mode with an Agilent 1100 series HPLC with autosampler.
- the column was usually a Water Xterra MS C18, 3.0 x 50 mm, 5 ⁇ m.
- the flow rate was 1 mL/min, and the injection volume was 10 ⁇ L.
- UV detection was in the range 210-400 nm.
- the mobile phase consisted of solvent A (water plus 0.06% TFA) and solvent B (acetonitrile plus 0.05% TFA) with a gradient of 100% solvent A for 0.7 min changing to 100% solvent B over 3.75 min, maintained for 1.1 min, then reverting to 100% solvent A over 0.2 min.
- Preparative HPLC purifications were usually performed using a mass spectrometry directed system.
- Tetramethylsilane (TMS) was used as internal reference in CD 3 Cl solutions, and residual CH 3 OH peak or TMS was used as internal reference in CD 3 OD solutions. Coupling constants (J) were reported in hertz (Hz). Chiral analytical chromatography was performed on one of Chiralpak AS, Chiralpak AD, Chiralcel OD, Chiralcel IA, or Chiralcel OJ columns (250x4.6 mm) (Daicel Chemical Industries, Ltd.) with noted percentage of either ethanol in hexane (%Et/Hex) or isopropanol in heptane (%IPA/Hep) as isocratic solvent systems.
- Chiral preparative chromatography was conducted on one of Chiralpak AS, Chiralpak AD, Chiralcel OD, Ciralcel IA, or Chiralcel OJ columns (20x250 mm) (Daicel Chemical Industries, Ltd.) with desired isocratic solvent systems identified on chiral analytical chromatography or by supercritical fluid (SFC) conditions.
- SFC supercritical fluid
- Abbreviations used herein include: -C(O)CH 3 (Ac); acetic acid (AcOH; HOAc); -OC(O)CH 3 (OAc); aqueous (aq); benzyloxycarbonyl (Cbz); (dba) dibenzylideneacetone; tris (dibenzylidineacetone)dipalladium (Pd 2 (dba) 3 ); N , N -diisopropylethylamine (DIPEA); N ; N- dimethylformamide (DMF); dimethylsulfide (DMS); 1,1'- bis (diphenylphosphino)ferrocene (dppf , DPPF); ethyl acetate (EtOAc); diethyl ether (ether or Et 2 O); petroleum ether (PE); gram(s) (g); hexane (Hex); hour(s) (h or hr); hexamethylphosphoramide (
- Step A 6-Oxo-5, 6, 7, 8-tetrahydronaphthalene-2-carbonitrile
- the 5-bromo-2 tetralone (2.0 g, 8.9 mmol), tetrakis(triphenylphosphine)palladium (0.62 g, 0.53 mmol) and zinc cyanide (0.73 g, 6.2 mmol) were added to 4 ml DMF in a 20 ml microwave tube.
- the mixture was degassed and microwaved at 80°C for 30 mins.
- TLC showed no starting material left and the mixture was diluted with ethyl acetate and washed with ammonium hydroxide (2M, x 4 ml).
- the organic layer was separated and dried over Na 2 SO 4 then filtered. The solvent was evaporated under reduced pressure.
- StepB tert -Butyl 4-(6-cyano-1,2,3,4-tetrahydronaphthalen-2-yl)piperazine-1-carboxylate
- Titanium (IV) isopropoxide (0.21 ml, 0.73 mmol), 6-oxo-5,6,7, 8-tetrahydronaphthalene-2-carbonitrile (100mg, 0.58 mmol), and tert -butyl piperazine-1-carboxylate(110 mg, 0.58 mmol) were stirred at room temperature.
- ethanol (10 ml) and sodium cyanoborohydride (25.7 mg, 0.409 mmol) were added to the mixture and stirred for 16 hrs.
- LC-MS showed incomplete formation of product. More sodium cyanoborohydride (77 mg, 1.23 mmol) and 2 drops of HOAc were added and stirred overnight.
- Step C 6-Piperazin-1-yl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
- Step A 5-(1,3-Dioxolan-2-ylmethyl)-2-benzofuran-1(3 H )-one
- bromo(1,3-dioxolan-2-ylmethyl)zinc solution (1.03 L, 516 mmol) was added via canula and the mixture was again degassed three times. The mixture was then heated at 85 °C for 5 h. Analysis by HPLC-MS indicated the reaction was not complete. The mixture was stirred at 85 °C for 5 more h. The mixture was then allowed to return to room temperature for overnight. 2-methylTHF (2L) and brine were added, and the mixture was stirred for 5 min. The layers were separated and the aqueous layer was extracted again with 2-methylTHF. The organic layers were combined, washed three times with brine (4L each), dried over MgSO 4 , filtered, and concentrated.
- a 4-neck, 22-L, round bottom flask equipped with a mechanical stirrer, thermocouple, nitrogen bubbler, and condenser was charged with 5-bromophthalide (650 g, 3.0 mol), allyltri-n-butyltin (1200 g, 3.6 mol), tetrakis(triphenylphosphine)palladium (100 g, 0.089 mol), lithium chloride (250 g, 5.9 mol) and toluene (8.8 L).
- the mixture was evacuated and flushed with nitrogen 3 times and then was stirred at 100 °C for 4 hours. After slowly cooling to ambient temperature, the mixture was filtered and concentrated.
- Step B 5-(2-Hydroxyethyl)-2-benzofuran-1(3 H )-one
- Step C 5-(2-Bromoethyl)-2-benzofuran-1(3 H )-one
- Step A 1,1-Dimethylethyl-4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazine-1-carboxylate
- Step B 5-(2-Piperazin-1-ylethyl)-2-benzofuran-1(3 H )-one hydrochloride
- Step B 5-Bromo-4-methyl-2-benzofuran-1(3 H )-one
- Step C 4-Methyl-5-prop-2-en-1-yl-2-benzofuran-1(3 H )-one
- Step D (4-Methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde
- Step E 1,1-Dimethylethyl-4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ehyl]piperazine-1-carboxylate
- Step F 4-Methyl-5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3 H )-one hydrochloride
- 1,1-Dimethylethyl-4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazine-1-carboxylate (245 mg) was treated with 4N HCl in dioxane solution and the reaction was monitored until completion. The mixture was concentrated to afford 4-methyl-5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3 H )-one hydrochloride.
- the hydrochloride can be converted to free base as needed by partitioning between organic solvent (EtOAc, DCM, or 30%IPA/CHCl 3 ) and saturated Na 2 CO 3 solution.
- Step A 4-Methyl-5-prop-2-en-1-yl-2-benzofuran-1(3 H )-one
- Step B (4-Methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetic acid
- Step C 1,1-Dimethylethyl (4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetate
- Step E 2-(4-Methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)propanoic acid
- Step F 5-(2-Hydroxy-1-methylethyl)-4-methyl-2-benzofuran-1(3H)-one
- Step G 2-(4-Methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)propanal
- Step B 4-Methyl-5-(1-methyl-2-piperazin-1-ylethyl)-2-benzofuran-1(3 H )-one
- Step A 6-Bromo-3-methyl-3,4-dihydro-1 H -isochromen-1-one
- Methyl Lithium (29 ml, 46 mmol) was added slowly via syringe to the cooled solution in order to make the lithio carboxylate. The resulting solution was stirred for 10 minutes and then transferred via cannula to the LDA solution at -78 °C. The resulting bright red solution was stirred at -78°C for an additional 1 hour before being quenched with anhydrous acetaldehyde (7.9 ml, 140 mmol) (color changed from red to orange to clear yellow) and the reaction was then taken out of the dry ice acetone bath and allowed to stir for an additional 1 hour.
- Step B 6-(1,3-Dioxolan-2-ylmethyl)-3-methyl-3,4-dihydro-1 H -isochromen-1-one
- a sealed tube was charged with aryl bromide, palladium(II) acetate (0.028 g, 0.12 mmol) and tri-t-butylphosphine-BF 4 complex (0.072 g, 0.249 mmol) and sealed.
- the tube was evacuated and refilled with nitrogen before DMF (12 ml) and 6-bromo-3-methyl-3,4-dihydro-1 H -isochromen-1-one (0.75 g, 3.1 mmol) were added followed by bromo(1,3-dioxolan-2-ylmethyl)zine (6.2 ml, 3.1 mmol).
- Step C tert -Butyl 4-[2-(3-methyl-1-oxo-3,4-dihydro-1H-isochromen-6-yl)ethyl]piperazine-1-carboxylate
- Step D 3-Methyl-6-[2-(piperazin-1-yl)ethyl]-3,4-dihydro-1 H -isochromen-1-one hydrochloride
- Step A (3 S )-6-Bromo-3-methyl-3,4-dihydro-1 H -isochromen-1-one
- Step B (3S)-6-(1,3-Dioxolan-2-ylmethyl)-3-methyl-3,4-dihydro-1 H -isochromen-1-one
- (3S)-6-(1,3-dioxolan-2-ylmethyl)-3-methyl-3,4-dihydro-1 H -isochromen-1-one was obtained using the procedure described for the synthesis of 6-(1,3-dioxolan-2-ylmethyl)-3-methyl-3,4-dihydro-1 H -isochromen-1-one utilizing the chiral S-enantiomer as the starting material.
- Step C tert -Butyl 4- ⁇ 2-[(3 S )-3-methyl-1-oxo-3,4-dihydro-1 H -isochromen-6-yl]ethyl ⁇ piperazine-1-carboxylate
- tert -Butyl 4- ⁇ 2-[(3 S )-3-methyl-1-oxo-3,4-dihydro-1 H -isochromen-6-yl]ethyl ⁇ piperazine-1-carboxylate was obtained using the procedure described for the synthesis of tert -butyl 4- ⁇ 2-[3-methyl-1-oxo-3,4-dihydro-1 H -isochromen-6-yl]ethyl ⁇ piperazine-1-carboxylate utilizing the chiral S-enantiomer as the starting material in the reaction.
- Step D (3 S )-3-Methyl-6-[2-(piperazin-1-yl)ethyl]-3,4-dihydro-1 H -isochromen-1-one
- Step B 5-(2-Piperazin-1-ylethyl)-2,1,3-benzoxadiazole
- tert -butyl 4-[2-(2,1,3-benzoxadiazol-5-yl)ethyl]piperazine-1-carboxylate tert -Butyl 4-[2-(2,1,3-benzoxadiazol-5-yl)ethyl]piperazine-1-carboxylate (470 mg, 1.4 mmol) was then dissolved in dioxane (10 mL) and added 7 mL of 4M HCl in dioxane. The reaction was stirred at room temperature overnight. Evaporated off all solvent and the residue was taken up in ethyl acetate basified with 1N NaOH.
- Step A tert -Butyl 4-(5-bromo-2,3-dihydro-1H-inden-2-yl)piperazine-1-carboxylate
- tert -butyl di(prop-2-en-1-yl)carbamate (0.74 mL, 3.4 mmol) was dissolved in dichloromethane (10 mL). The solution was cooled to -78 °C. To above solution was bubbled ozone for 15 min. The solution turned into light blue and the color stayed. To above solution was bubbled nitrogen to remove excess ozone until the solution turned into colorless.
- Step B tert -Butyl 4-(5-cyano-2,3-dihydro-1H-inden-2-yl)piperazine-1-carboxylate
- Step C 4-(5-Cyano-2.3-dihydro-1 H -inden-2-yl)piperazin-1-ium chloride
- Step A [3-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]acetic acid
- Step B 2-(7-Oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-1H-isoindole-1,3(2H)-dione
- Step C tert -Butyl4-[7-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl]piperazine-1-carboxylate
- Step D 2- ⁇ 7-[4-(Trifluoroacetyl)piperazin-1-yl]-5,6,7,8-tetrahydrophthalen-2-yl ⁇ -1H-isoindole-1,3(2H)-dione
- Step E 2- ⁇ 3-Nitro-7-[4-(trifluoroacetyl)piperazin-1-yl]-5,6,7,8-tetrahydronaphthalen-2-yl ⁇ -1H-isoindole-1,3(2H)-dione
- Step F tert -Butyl 4-(7-amino-6-nitro-1,2,3,4-tetrahydronaphtalen-2-yl)piperazine-1-carboxylate
- Step G tert -Butyl 4-(1-oxido-5.6,7,8-tetrahydronaphtho[2,3-c][1,2,5]oxadiazol-6-yl)piperazine-1-carboxylate
- Step H tert -Butyl 4-(5,6,7,8-tetrahydronaphtho[2,3-c][1,2,5]oxadiazol-6-yl)piperazine-1-carboxylate
- Step I 6-Piperazin-1-yl-5,6,7,8-tetrahydronaphtho[2,3-c][1,2,5]oxadiazole hydrochloride
- Step B 1-[2-(6-Nitropyridin-3-yl)ethyl]piperazine hydrochloride
- LC showed formation of the desired product, which was separated by silica gel flash chromatography (Hexane:EtOAc).
- LC-MS (IE, m / z ): 337 [M + 1] + .
- the material was further treated with 4N HCl in dioxane, and the crude 1-[2-(6-nitropyridin-3-yl)ethyl]piperazine hydrochloride was carried on without further purification.
- LC-MS (IE, m / z ): 237 [M + 1] + .
- Lithium chloride (0.64 g, 15.1 mmol) was added to a mixture of 5-bromo-2,1,3-benzoxadiazole (1.0 g, 5.0 mmol), tetrakis(triphenylphosphine)palladium (0.29 g, 0.25 mmol) and allyl tri-n-butyltin (1.87 ml, 6.0 mmol) in 30 ml toluene then refluxed for 3 hours. The reaction was filtered, concentrated, and loaded into an ISCO 120 gm Redi-Sep then eluted with a gradient of 0-50% ethyl acetate/hexane.
- Step B (1E)-1-[(Methyloxy)methylidene]-2,3-dihydro-1H-indene-4-carbonitrile
- Step D tert -Butyl 4-[(4-cyano-23-dihydro-1H-inden-1-yl)methyl]piperazine-1-carboxylate
- Step B 4-Formyl-3,4-dihydro-2 H -chromene-7-carbonitrile
- Step A (5E)-5-(Methoxymethylidene)-5,6,7-8-tetrahydronaphthalene-2-carbonitrile
- Step B 5-Formyl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
- Step A Methyl (3-fluoro-4-hydroxyphenyl) acetate
- Step B Methyl (3-fluoro-4- ⁇ [(trifluoromethyl)sulfonyl]oxy ⁇ phenyl)acetate
- Step C Methyl (4-cyano-3-fluorophenyl) acetate
- the aqueous layer was re-extracted with ethyl acetate (1 x 100 mL), the organic portions were combined and dried over magnesium sulfate. The dry organics were then filtered and evaporated to dryness under reduced pressure and excess dimethylformamide was removed by evaporation in vacuo at 65 °C for 1.5 h to yield the crude title compound (42 g).
- Step A Di- tert -butyl (4-cyano-2,5-difluorophenyl)propanedioate
- Step B (4-Cyano-2,5-difluorophenyl)acetic acid
- Step A Di- tert -butyl(3-bromo-4-cyanophenyl)malonate
- Step B (3-Bromo-4-cyanophenyl) acetic acid
- Step A Ethyl (3-methoxy-4- ⁇ [(trifluoromethyl)sulfonyl]oxy ⁇ phenyl)acetate
- Step B Ethyl (4-cyano-3-methoxyphenyl) acetate:
- the aqueous layer was re-extracted with ethyl acetate (2 x 100 mL), the organic portions were combined and dried over magnesium sulfate. The dry organics were then filtered and evaporated to dryness under reduced pressure and excess dimethylformamide was removed by evaporation in vacuo at 65 °C for 1.5 h to yield the crude title compound (20 g).
- the crude product was purified through silica gel chromatography (ethyl acetate/hexanes, 2:3) to yield the title nitrile.
- Step D 4-(1-Hydroxypropan-2-yl)-2-methoxybenzonitrile
- Step B 4-(1-Hydroxy-2-methylpropan-2-yl)-2-methoxybenzonitrile
- Step A 6-Fluoro-7-hydroxy-2,3-dihydro-4 H -chromen-4-one
- Step B 6-Fluoro-4-oxo-3,4-dihydro-2 H -chromen-7-yl trifluoromethanesulfonate
- Step C 6-Fluoro-4-oxo-3,4-dihydro-2 H -chromene-7-carbonitrile
- Step D (4E)-6-fluoro-4-(methyoxymethylidene)-3,4-dihydro-2 H -chromene-7-carbonitrile
- Step E 6-Fluoro-4-formyl-3,4-dihydro-2 H -chromene-7-carbonitrile
- Step B 5-Fluoro-2-methoxy-4-(2-oxoethyl)benzonitrile
- Step A tert -butyl [(2S)-6-cyano-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate
- the enantiomers were separated using the AD column with 5% EtOH/heptane.
- the first peak was assumed as the tert -butyl [(2S)-6-cyano-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate, and the second peak was assumed as the tert -butyl [(2R)-6-cyano-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate.
- Step B (6S)-6-Amino-5,6,7,8-tetrahydronaphthalene-2-carbonitrile
- (6R)-6-piperazin-1-yl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile was prepared following the same procedure as INTERMEDIATE 31a from tert -butyl (6-cyano-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate tert -butyl [(2R)-6-cyano-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate.
- Step D 4-(2-Oxoethyl)-2-(trifluoromethoxy)benzonitrile
- Step B 3-Fluoro-2-methoxy-4-(2-oxoethyl)benzonitrile
- Step B 4-(2-Oxoethyl)naphthalene-1-carbonitrile
- Step B 2-(Ethoxy)4-(2-oxoethyl)- benzonitrile
- Step B 4-(2-Oxoethyl)-2,3,5-trifluorobenzonitrile
- Step A tert -Butyl methyl (2-chloro-4-cyano-3-fluorophenyl)malonate
- the first product fractions were a mixture with some of the minor t-butyl methyl (2-chloro-6-cyano-3-fluorophenyl)malonate side product isomer (900 mg, mostly desired title product by NMR), then later fractions were clean desired title isomer.
- Step B 3-Chloro -4-(2-hydroxethyl)-2-methoxybenzonitrile
- Step A t-Butvl methyl (4-cyano-3-fluoro-2-methylphenyl)malonate
- Step A 4-Fluoro-5-iodo-2-methoxybenzonitrile
- Step B 4-Fluoro-2-methoxy-5-(prop-2-en-1-yl)benzonitrile
- Step D 4-Fluoro-2-methoxy-5-(2-oxoethyl)benzonitrile
- Step A 1-[2-(4-bromophenyl)ethyl]-4-[2-(4-nitrophenyl)ethyl]piperazine
- Step B 4-(2- ⁇ 4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl ⁇ ethyl)benzonitrile
- Hunig's Base (3.0 ml, 17 mmol) was added to a stirred solution of piperazine (250 mg, 2.9 mmol) and 1-bromo-4-(2-bromoethyl) benzene (0.89 ml, 5.8 mmol) at 50 °C for 16 hours. The reaction was then poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated and dried over Na 2 SO 4 and evaporated to dryness.
- Step B 4,4'-(Piperazine-1,4-diyldiethane-2,1-diyl)dibenzonitrile:
- Tetrakis(triphenylphosphine)palladium 15 mg, 0.013 mmol
- zinc cyanide 52 mg, 0.44 mmol
- 1,4-bis[2-(4-bromophenyl)ethyl]piperazine 100 mg, 0.22 mmol
- Zn(CN) 2 52 mg, 0.44 mmol
- microwaved for another 1hour The reaction mixture was cooled and filtered. To the filtrate was added 1 N NaOH then extracted with ethyl acetate.
- Step B Methyl_(2S)-3-(4-nitrophenyl)-2- ⁇ 4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl ⁇ propanoate
- Step A 2-( tert -Butoxymethyl)-1,4-bis[2-(4-nitrophenyl)ethyl]piperazine
- StepB ⁇ 1,4-Bis[2-(4-nitrophenyl)ethyl]piperazin-2-yl ⁇ methanol
- Step A 1-(2-(4-Nitrophenyl)ethyl]-4-(2-(4-nitrophenyl)propanoyl]piperazine
- Residue was purified by prep-TLC plate with 5% (NH 4 OH:MeOH 9:1) in DCM to yield 1-[2-(4-nitrophenyl)ethyl]-4-[2-(4-nitrophenyl)propanoyl]piperazine (100 mg, 0.24 mmol).
- Step B 1-[2-(4-Nitrophenyl)ethyl]-4-[2-(4-nitrophenyl)propyl]piperazine
- Step B 1-[2-(4-Nitrophenyl)ethyl]-4- ⁇ 2-[4-nitro-2-(trifluoromethyl)phenyl]ethyl ⁇ piperazine
- Titanium(IV) isopropoxide (1.8 ml, 6.0 mmol) was added to a mixture of 1-[2-(4-nitrophenyl)ethyl]piperazine hydrochloride (0.82 g, 3.0 mmol) and 2,1,3-benzodiazole-5-yl acetaldehyde (0.49 g, 3mmol) in ethanol (5 ml) then added sodium cyanoborohydride (0.75 g, 12.0 mmol) and 2 drops of acetic acid. The reaction was stirred at room temperature for 16 hours. The reaction mixture was filtered and poured into 1N NaOH then extracted with ethyl acetate.
- Step B Ethyl 3-(4-cyano-3-methoxyphenyl)oxirane-2-carboxylate
- Step D 2-Methoxy-4-(2- ⁇ 4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl ⁇ ethyl)benzonitrile
- Step B Ethyl 3-(4-cyano-2-methylphenyl)oxirane-2-carboxylate
- Step D 3-Methyl-4-((E)-2- ⁇ 4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl ⁇ vinyl)benzonitrile
- Step E 3-Methyl-4-(2- ⁇ 4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl ⁇ ethyl)benzonitrile
- Step B Ethyl 3-(4-cyano-3-methylphenyl)oxirane-2-carboxylate
- Step D 2- Methyl-4-(2- ⁇ 4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl ⁇ ethyl)benzonitrile
- Step B 4-(2,3-Dihydroxypropyl)-2,6-difluorobenzonitrile
- Step D 2.6-Difluoro-4-(2- ⁇ 4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl ⁇ ethyl)benzonitrile
- Step B 4-(2,3-Dihydroxypropyl)-3-methoxybenzonitrile
- Step D 3-Methoxy-4-(2- ⁇ 4-(4-nitrophenyl)ethyl]piperazin-1-yl ⁇ ethyl)benzonitrile
- Step B 4-(2,3-Dihydroxypropyl)-2-fluorobenzonitrile
- Step D 2-Fluoro-4-(2- ⁇ 4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl ⁇ ethyl)benzonitrile:
- Step A tert -Butyl 4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-3-(trifluoromethyl)piperazine-1-carboxylate
- Step B 5- ⁇ 2-[2-(Trifluoromethyl)piperazin-1-yl]ethyl ⁇ -2-benzofuran-1(3 H )-one
- Step C 2-Methoxy-4-(2- ⁇ 4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-3-(tri fluoromethyl)piperazin-1-yl ⁇ ethyl)benzonitrile
- Step A tert -Butyl 4-[2-(4-cyano-3-methoxyphenyl)ethyl]-3-(trifluoromethyl)piperazine-1-carboxylate
- reaction mixture was concentrated and purified by column chromatography (4->30% ethyl acetate:hexanes) to provide tert -butyl 4-[2-(4-cyano-3-methoxyphenyl)ethyl]-3-(trifluoromethyl)piperazine-1-carboxylate.
- LC-MS (IE, m / z ): 414.4 [M + 1] + .
- Step B 2-methoxy-4- ⁇ 2-[2-(trifluoromethyl)piperazin-1-yl]ethyl ⁇ benzonitrile
- Step C 2-Methoxy-4- ⁇ 2-(4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-2-(trifluoromethyl)piperazin-1-yl ⁇ ethyl)benzonitrile
- Step C tert -Butyl 4-[2-(4-cyano-3-fluorophenyl)ethyl]piperazine-1-carboxylate
- Step D tert -Butyl 4- ⁇ 2-[4-cyano-3-(methylthio)phenyl]ethyl ⁇ piperazine-1-carboxylate
- Step E 2-(Methylthio)4-(2- ⁇ 4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl ⁇ ethyl)benzonitrile
- Step A tert -Butyl 4- ⁇ 2-[4-cyano-3-(methylamino)phenyl]ethyl ⁇ piperazine-1-carboxylate
- Step C 2-(Methylamino)-4-(2- ⁇ 4-[2-(1-oxo-1,3-dihvdro-2-benzofuran-5-yl)ethyl]piperazin-1-yl ⁇ ethyl)benzonitrile
- Step E tert -Butyl 4- ⁇ 2-[4-cyano-3-(difluoromethoxy)phenyl]ethyl ⁇ piperazine-1-carboxylate:
- Step F 2-(Difluoromethoxy)-4-(2- ⁇ 4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl ⁇ ethyl)benzonitrile
Description
- The Renal Outer Medullary Potassium (ROMK) channel (Kirl.l) (see e.g., Ho, K., et al., Cloning and expression of an inwardly rectifying ATP-regulated potassium channel, Nature, 1993, 362(6415): p. 31-8.1, 2; and Shuck, M.E., et al., Cloning and characterization of multiple forms of the human kidney ROM-K potassium channel, J Biol Chem, 1994, 269(39): p. 24261-70) is a member of the inward rectifier family of potassium channels expressed in two regions of the kidney: thick ascending loop of Henle (TALH) and cortical collecting duct (CCD) (see Hebert, S.C., et al., Molecular diversity and regulation of renal potassium channels, Physiol Rev, 2005, 85(1): p. 319-713). At the TALH, ROMK participates in potassium recycling across the luminal membrane which is critical for the function of the Na+/K+/2Cl- co-transporter, the rate-determining step for salt reuptake in this part of the nephron. At the CCD, ROMK provides a pathway for potassium secretion that is tightly coupled to sodium uptake through the amiloride-sensitive sodium channel (see Reinalter, S.C., et al., Pharmacotyping of hypokalaemic salt-losing tubular disorders, Acta Physiol Scand, 2004, 181(4): p. 513-21; and Wang, W., Renal potassium channels: recent developments, Curr Opin Nephrol Hypertens, 2004, 13(5): p. 549-55). Selective inhibitors of the ROMK channel (also referred to herein as inhibitors of ROMK or ROMK inhibitors) are predicted to represent novel diuretics for the treatment of hypertension and other conditions where treatment with a diuretic would be beneficial with potentially reduced liabilities (i.e., hypo- or hyperkalemia, new onset of diabetes, dyslipidemia) over the currently used clinical agents (see Lifton, R.P., A.G. Gharavi, and D.S. Geller, Molecular mechanisms of human hypertension, Cell, 2001, 104(4): p. 545-56). Human genetics (Ji, W., et al., Rare independent mutations in renal salt handling genes contribute to blood pressure variation, Nat Genet, 2008, 40(5): p. 592-9; and Tobin, M.D., et al., Common variants in genes underlying monogenic hypertension and hypotension and blood pressure in the general population, Hypertension, 2008, 51(6): p. 1658-64) and genetic ablation of ROMK in rodents (see Lorenz, J.N., et al., Impaired renal NaCl absorption in mice lacking the ROMKpotassium channel, a model for type II Bartter's syndrome, J Biol Chem, 2002, 277(40): p. 37871-80 and Lu, M., et al., Absence of small conductance K+ channel (SK) activity in apical membranes of thick ascending limb and cortical collecting duct in ROMK (Bartter's) knockout mice, J Biol Chem, 2002, 277(40): p. 37881-7) support these expectations. To our knowledge, the first small molecule selective inhibitors of ROMK were reported from work done at Vanderbilt University as described in Lewis, L.M., et al., High-Throughput Screening Reveals a Small-Molecule Inhibitor of the Renal Outer Medullary Potassium Channel and Kir7.1, Mol Pharmacol, 2009, 76(5): p. 1094-1103. Further ROMK inhibitors were described in G. Bhave, et al., Development of a Selective Small-Molecule Inhibitor of Kir1.1, the Renal Outer Medullary Potassium Channel, MOLECULAR PHARMACOLOGY, 2011, Vol. 79(1), 42-50.
- However, continuing discovery of selective small molecule inhibitors of ROMK is still needed for the development of new treatments for hypertension and related disorders.
- The present invention provides compounds of Formula I
- The present invention is directed to compounds having structural Formula I:
Z1 is selected from the group consisting of:
R1 and R2 are each independently selected from the group consisting of -H, -F, -Cl, -Br, -C3-C6cycloalkyl, -OR8, -SR8, -SOR8, -SO2R8, -(CH2)nOR8 and -C1-6alkyl optionally substituted with 1-3 of -F;
one of R3a and R3b is selected from the group consisting of -CN -NO2 and tetrazoly, and the other is R3c wherein R3c selected from the group consisting of -H, -F, -Cl, -Br, -CH3, -S-CH3, -NH-CH3, -O-cyclopropyl and -OC1-3alkyl optionally substituted with 1-3 of -F;
one of R4a and R4b is selected from the group consisting of CN, -NO2 and tetrazolyl, and the other is R4c wherein R4c is selected from the group consisting of -H, -F, -Cl, -Br, -CH3, -S-CH3, -NH-CH3, -O-cyclopropyl and -OC1-3alkyl optionally substituted with 1-3 of -F; Ra, Raa, Rb and Rbb are each independently selected from the group consisting of -H, -F, -Cl, -CH3 optionally substituted with 1 to 3 of -F, and -OCH3 optionally substituted with 1 to 3 of -F;
Rc and Rd are each independently selected from the group consisting of-H, -F, -Cl, -C1-6alkyl optionally substituted with 1 to 3 of -F, -C3-6cycloalkyl and -OC1-6alkyl optionally substituted with 1 to 3 of -F;
Re and Rf are each independently selected from the group consisting of -H and -CH3;
X and X1 are each independently selected from -H and -C1-6alkyl, or X1 is joined together with Z1 and the carbon to which both are attached to form a fused ring system selected from the group consisting of:
or Y1 is joined together with Z2 and the carbon to which both are attached to form a fused ring system selected from the group consisting of:
or R5 is joined together with Z1 and the intervening carbons to which each is attached to form a fused ring system selected from:
R8 is selected from the group consisting of -C1-6alkyl and -C3-6cycloalkyl. In an embodiment of this inventions are compounds of Formula I or Formula II
Z1 is selected from the group consisting of: - Z2 is selected from the group consisting of:
Y and Y1 are each independently selected from -H and -C1-6alkyl, or Y1 is joined together with Z2 and the carbon to which both are attached to form a fused ring system selected from the group consisting of:
R6 is selected from -H, -CH3, -C1-6 alkyl and -C(O)OC1-3alkyl,
or R6 is joined together with Z2 and the intervening carbons to which each is attached to form a fused ring system selected from: -
- In Embodiment B are compounds of Formula I or II and the pharmaceutically acceptable salts thereof wherein Z1 is
-
-
- In another embodiment are compounds of Formulas I or II, and Embodiments A, B, C or D and the pharmaceutically acceptable salts thereof wherein R7 is -H.
-
- In another embodiment are compounds of Formulas I or II, and Embodiments A, B, C or D and the pharmaceutically acceptable salts thereof wherein R1 and R2 are independently selected from -H and -CH3.
- In another embodiment are compounds of Formulas I or II, and Embodiments A, B, C or D and the pharmaceutically acceptable salts thereof wherein R3a and R4a are independently selected from the group consisting of -CN and -NO2, and R3b and R4b is are independently selected from the group consisting of -H, -F, -Cl, -Br, -CH3, -S-CH3, -NH-CH3, -O-cyclopropyl and -OC1-3alkyl optionally substituted with 1-3 of -F. In a further embodiment, when R3a is -NO2 then R3b and Ra are both -H.
- In another embodiment are compounds of Formulas I or II, and Embodiments A, B, C or D and the pharmaceutically acceptable salts thereof wherein when R3a is -CN then R3b is selected from -Cl, -F, -OCH3 and -OCH2CH3; and when R 4a is -CN then R 4b is selected from -Cl, -F, -OCH3 and -OCH2CH3. Preferably, when R3b is -CN then R3a is selected from -F and -OCH3; and when R4b is -CN then R4a is selected from -F and -OCH3.
- In another embodiment are compounds of Formulas I or II, and Embodiments A, B, C or D and the pharmaceutically acceptable salts thereof wherein R4a is tetrazolyl.
- In another embodiment are compounds of Formulas I or II, and Embodiments A, B, C or D and the pharmaceutically acceptable salts thereof wherein Ra and Rb are each independently selected from the group consisting of -H, -F, -Cl, -CH3 optionally substituted with 1 to 3 of -F, and -OCH3 optionally substituted with 1 to 3 of -F; and more particularly -H, -F, and -CH3.
- In another embodiment are compounds of Formulas I or II, and Embodiments A, B, C or D and the pharmaceutically acceptable salts thereof wherein Raa and Rbb are each independently -H or -F; and more particularly both are -H.
- In another embodiment are compounds of Formulas I or II, and Embodiments A, B, C or D and the pharmaceutically acceptable salts thereof wherein Rc and Rd are each independently selected from the group consisting of -H, -F, -Cl, -CH3 optionally substituted with 1 to 3 of -F, and -OCH3 optionally substituted with 1 to 3 of -F; and more particularly -H, -F, and -CH3.
- In another embodiment are compounds of Formulas I or II, and Embodiments A, B, C or D and the pharmaceutically acceptable salts thereof wherein X, X1 , Y and Y1 are each -H.
- In another embodiment are compounds of Formulas I or II, and Embodiments A, B, C or D and the pharmaceutically acceptable salts thereof wherein R5 and R6 are selected from -H and -CH3.
- In another embodiment are compounds of Formula I and the pharmaceutically acceptable salts thereof wherein X1 is joined together with Z1 and the carbon to which both are attached to form a fused ring system.
- In another embodiment are compounds of Formula I and the pharmaceutically acceptable salts thereof wherein R5 is joined together with Z1 and the intervening carbons to which each is attached to form a fused ring system.
- In another embodiment are compounds of Formulas I or II, and Embodiments A, B, C or D and the pharmaceutically acceptable salts thereof wherein Y1 is joined together with Z2 and the carbon to which both are attached to form a fused ring system. In a class of this embodiment, the fused ring system is:
- In another embodiment are compounds of Formulas I or II, and Embodiments A, B, C or D and the pharmaceutically acceptable salts thereof wherein R6 is joined together with Z2 and the intervening carbons to which each is attached to form a fused ring system. In a class of this embodiment, the fused ring system is:
- As used herein except if noted otherwise, "alkyl" is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Commonly used abbreviations for alkyl groups are used throughout the specification. For example the term "C1-6 alkyl" (or "C1-C6 alkyl"), means linear or branched chain alkyl groups, including all isomers, having the specified number of carbon atoms and includes all of the hexyl and pentyl isomers as well as n-, iso-, sec- and tert-butyl (butyl, s-butyl, i-butyl, i-butyl; Bu = butyl), n- and i-propyl (Pr = propyl), ethyl (Et) and methyl (Me).
- "Cycloalkyl" is a cyclized alkyl ring having the indicated number of carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cycloalkyl ring may be substituted on any available carbon which results in the creation of a stable structure, including the ring carbon which serves as the point of attachment to the rest of the molecule.
- In some instances the number of substituents which may be optionally present on a moiety is specified, for example but not limited to, 1 to 3 of -F (fluoro). For example, an alkyl group that can be optionally substituted with 1-3 of -F includes, but is not limited to, -CH3, -CH2F, -CHF2, -CF3, -CH2CH3, -CH2-CH2F -CH2-CHF2, -CHF-CH2F, -CH2CF3, -CHF-CHF2, -(CH2)2CH3, -CH(CF3)-CH3, -(CH2)3-CF3, -(CH2)2CH(CF3)CH3, and -(CH2)5-CF3, as appropriate for the defined number of carbon atoms for the given alkyl group.
- Halo or halogen refers to -F (fluoro), -Cl (chloro), -Br (bromo) and -I (iodo). Preferred halogens are -F and -Cl.
- Unless expressly depicted or described otherwise, variables depicted in a structural formula with a "floating" bond, such as each of substituents Ra, Rb, Rc, Rd, Re and Rf in structural Formulas I and II, are permitted on any available carbon atom in the ring to which each is attached.
- The present invention encompasses all stereoisomeric forms of the compounds of Formula I. Centers of asymmetry that are present in the compounds of Formula I can all independently of one another have (R) configuration or (S) configuration. When bonds to the chiral carbon are depicted as straight lines in the structural Formulas of the invention, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the Formula. Similarly, when a compound name is recited without a chiral designation for a chiral carbon, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence individual enantiomers and mixtures thereof, are embraced by the name. The production of specific stereoisomers or mixtures thereof may be identified in the Examples where such stereoisomers or mixtures were obtained, but this in no way limits the inclusion of all stereoisomers and mixtures thereof from being within the scope of this invention.
- The invention includes all possible enantiomers and diastereomers and mixtures of two or more stereoisomers, for example mixtures of enantiomers and/or diastereomers, in all ratios. Thus, enantiomers are a subject of the invention in enantiomerically pure form, both as levorotatory and as dextrorotatory antipodes, in the form of racemates and in the form of mixtures of the two enantiomers in all ratios. In the case of a cis/trans isomerism the invention includes both the cis form and the trans form as well as mixtures of these forms in all ratios. The preparation of individual stereoisomers can be carried out, if desired, by separation of a mixture by customary methods, for example by chromatography or crystallization, by the use of stereochemically uniform starting materials for the synthesis or by stereoselective synthesis. Optionally a derivatization can be carried out before a separation of stereoisomers. The separation of a mixture of stereoisomers can be carried out at an intermediate step during the synthesis of a compound of Formula I or it can be done on a final racemic product. Absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing a stereogenic center of known configuration. Where compounds of this invention are capable of tautomerization, all individual tautomers as well as mixtures thereof are included in the scope of this invention. The present invention includes all such isomers, as well as salts, solvates (including hydrates) and solvated salts of such racemates, enantiomers, diastereomers and tautomers and mixtures thereof.
- Reference to the compounds of this invention as those of a specific formula or embodiment, e.g., Formula I and II and embodiments thereof, or any other generic structural formula or specific compound described or claimed herein, is intended to encompass the specific compound or compounds falling within the scope of the formula or embodiment, including salts thereof, particularly pharmaceutically acceptable salts, solvates of such compounds and solvated salt forms thereof, where such forms are possible unless specified otherwise.
- In the compounds of Formula I, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of Formula I. For example, different isotopic forms of hydrogen (H) include protium (1H) and deuterium (2H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds within Formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
- When the compounds of Formula I contain one or more acidic or basic groups the invention also includes the corresponding physiologically or toxicologically acceptable salts, in particular the pharmaceutically utilizable salts. Thus, the compounds of Formula I which contain acidic groups can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts or as ammonium salts. Examples of such salts include but are not limited to sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids. Compounds of Formula I which contain one or more basic groups, i.e. groups which can be protonated, can be used according to the invention in the form of their acid addition salts with inorganic or organic acids as, for example but not limited to, salts with hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, trifluoroacetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, etc. If the compounds of Formula I simultaneously contain acidic and basic groups in the molecule the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). Salts can be obtained from the compounds of Formula I by customary methods which are known to the person skilled in the art, for example by combination with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange from other salts. The present invention also includes all salts of the compounds of Formula I which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of physiologically (i.e., pharmaceutically) acceptable salts.
- Furthermore, compounds of the present invention may exist in amorphous form and/or one or more crystalline forms, and as such all amorphous and crystalline forms and mixtures thereof of the compounds of Formula I are intended to be included within the scope of the present invention. In addition, some of the compounds of the instant invention may form solvates with water (i.e., a hydrate) or common organic solvents. Such solvates and hydrates, particularly the pharmaceutically acceptable solvates and hydrates, of the instant compounds are likewise encompassed within the scope of this invention, along with un-solvated and anhydrous forms.
- Any pharmaceutically acceptable pro-drug modification of a compound of this invention which results in conversion in vivo to a compound within the scope of this invention is also within the scope of this invention. For example, esters can optionally be made by esterification of an available carboxylic acid group or by formation of an ester on an available hydroxy group in a compound. Similarly, labile amides can be made. Pharmaceutically acceptable esters or amides of the compounds of this invention may be prepared to act as pro-drugs which can be hydrolyzed back to an acid (or -COO- depending on the pH of the fluid or tissue where conversion takes place) or hydroxy form particularly in vivo and as such are encompassed within the scope of this invention. Examples of pharmaceutically acceptable pro-drug modifications include, but are not limited to, -C1-6alkyl esters and -C1-6alkyl substituted with phenyl esters.
- Accordingly, the compounds within the generic structural formulas, embodiments and specific compounds described and claimed herein encompass salts, all possible stereoisomers and tautomers, physical forms (e.g., amorphous and crystalline forms), solvate and hydrate forms thereof and any combination of these forms, as well as the salts thereof, pro-drug forms thereof, and salts of pro-drug forms thereof, where such forms are possible unless specified otherwise.
- The compounds of Formula I according to the invention are inhibitors of ROMK, and are therefore useful as diuretic and/or natriuretic agents. ROMK inhibitors help to increase urination and increase urine volume and also to prevent or reduce reabsorption of sodium in the kidneys leading to increased excretion of sodium and water. Therefore, the compounds are useful for treatment or prophylaxis of disorders that benefit from increased excretion of water and sodium from the body. Accordingly, an object of the instant invention is to provide a method for inhibiting ROMK comprising administering a compound of Formula I in a ROMK-inhibitory effective amount to a patient in need thereof. The inhibition of ROMK by the compounds of Formula I can be examined, for example, in any of the activity assays described below. Another object is to provide a method for causing diuresis, natriuresis or both, comprising administering a compound of Formula I in a therapeutically effective amount to a patient in need thereof.
- Due to their activity as diuretics and natriuretic agents, this invention further provides the use of compounds of Formula I in methods for treatment of, prevention of or reduction of risk for developing medical conditions that benefit from increased excretion of water and sodium, such as but not limited to one or more of hypertension, heart failure (both acute and chronic, also known as congestive heart failure) and/or other conditions resulting from excessive salt and water retention. It further includes the use of the compounds of Formula I in methods for treatment of, prevention of or reduction of risk for developing one or more disorders such as pulmonary arterial hypertension (PAH), cardiovascular disease, diabetes, endothelial dysfunction, diastolic dysfunction, stable and unstable angina pectoris, thromboses, restenosis, myocardial infarction, stroke, cardiac insufficiency, pulmonary hypertonia, atherosclerosis, hepatic cirrhosis, ascitis, pre-eclampsia, cerebral edema, nephropathy, nephrotic syndrome, acute and chronic kidney insufficiency, hypercalcemia, Dent's disease, Meniere's disease, edetamous states, and other conditions for which a diuretic would have therapeutic or prophylactic benefit. The compounds of the invention can be administered to a patient having, or at risk of having, one or more conditions for which a diuretic would have therapeutic or prophylactic benefit such as those described herein.
- In general, compounds that are ROMK inhibitors can be identified as those compounds which, when tested, have an IC50 of 5 µM or less, preferably 1 µM or less, and more preferably 0.25 µM or less, in at least one of the following assays: 1) the 86Rb+ Efflux Assay and 2) the Thallium Flux Assay. These assays are described in more detail further below.
- The dosage amount of the compound to be administered depends on the individual case and is, as is customary, to be adapted to the individual circumstances to achieve an optimum effect. Thus, it depends on the nature and the severity of the disorder to be treated, and also on the sex, age, weight and individual responsiveness of the human or animal to be treated, on the efficacy and duration of action of the compounds used, on whether the therapy is acute or chronic or prophylactic, or on whether other active compounds are administered in addition to compounds of Formula I. A consideration of these factors is well within the purview of the ordinarily skilled clinician for the purpose of determining the therapeutically effective or prophylactically effective dosage amount needed to prevent, counter, or arrest the progress of the condition. It is expected that the compound will be administered chronically on a daily basis for a length of time appropriate to treat or prevent the medical condition relevant to the patient, including a course of therapy lasting days, months, years or the life of the patient.
- In general, a daily dose of approximately 0.001 to 100 mg/kg, preferably 0.001 to 30 mg/kg, in particular 0.001 to 10 mg/kg (in each case mg per kg of bodyweight) is appropriate for administration to an adult weighing approximately 75 kg in order to obtain the desired results. The daily dose is preferably administered in a single dose or, in particular when larger amounts are administered, can be divided into several, for example two, three or four individual doses, and may be, for example but not limited to, 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 75 mg, 100 mg, etc., on a daily basis. In some cases, depending on the individual response, it may be necessary to deviate upwards or downwards from the given daily dose. Furthermore, the compound may be formulated for immediate or modified release such as extended or controlled release.
- The term "patient" includes animals, preferably mammals and especially humans, who use the instant active agents for the prohhylaxis or treatment of a medical condition. Administering of the drug to the patient includes both self-administration and administration to the patient by another person. The patient may be in need of treatment for an existing disease or medical condition, or may desire prophylactic treatment to prevent or reduce the risk for developing said disease or medical condition or developing long-term complications from a disease or medical condition.
- The term therapeutically effective amount is intended to mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, a system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. A prophylactically effective amount is intended to mean that amount of a pharmaceutical drug that will prevent or reduce the risk of occurrence of the biological or medical event that is sought to be prevented in a tissue, a system, animal or human by a researcher, veterinarian, medical doctor or other clinician. It is understood that a specific daily dosage amount can simultaneously be both a therapeutically effective amount, e.g., for treatment of hypertension, and a prophylactically effective amount, e.g., for prevention or reduction of risk of myocardial infarction or prevention and reduction of risk for complications related to hypertension.
- In the methods of treatment of this invention, the ROMK inhibitors may be administered via any suitable route of administration such as, for example, orally, parenterally, or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. Oral formulations are preferred, particularly solid oral dosage units such as pills, tablets or capsules.
- Accordingly, this invention also provides pharmaceutical compositions comprised of a compound of Formula I and a pharmaceutically acceptable carrier. For oral use, the pharmaceutical compositions of this invention containing the active ingredient may be in forms such as pills, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients, which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, mannitol, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc.
- Pharmaceutical compositions may also contain other customary additives, for example, wetting agents, stabilizers, emulsifiers, dispersants, preservatives, sweeteners, colorants, flavorings, aromatizers, thickeners, diluents, buffer substances, solvents, solubilizers, agents for achieving a depot effect, salts for altering the osmotic pressure, coating agents or antioxidants.
- Oral immediate-release and time-controlled release dosage forms may be employed, as well as enterically coated oral dosage forms. Tablets may be uncoated or they may be coated by known techniques for aesthetic purposes, to mask taste or for other reasons. Coatings can also be used to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
- Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients is mixed with water or miscible solvents such as propylene glycol, PEGs and ethanol, or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
- Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose.
- The instant invention also encompasses a process for preparing a pharmaceutical composition comprising combining a compound of Formula I with a pharmaceutically acceptable carrier. Also encompassed is the pharmaceutical composition which is made by combining a compound of Formula I with a pharmaceutically acceptable carrier. The carrier is comprised of one or more pharmaceutically acceptable excipients. Furthermore, a therapeutically effective amount of a compound of this invention can be used for the preparation of a medicament useful for inhibiting ROMK, for causing diuresis and/or natriuresis, and/or for treating, preventing or reducing the risk for any of the medical conditions described herein, in dosage amounts described herein.
- The amount of active compound of Formula I and/or its pharmaceutically acceptable salts in the pharmaceutical composition may be, for example but not limited to, from 0.1 to 200 mg, preferably from 0.1 to 50 mg, per dose on a free acid/free base weight basis, but depending on the type of the pharmaceutical composition and potency of the active ingredient it could also be lower or higher. Pharmaceutical compositions usually comprise 0.5 to 90 percent by weight of the active compound on a free acid/free base weight basis.
- The compounds of Formula I inhibit ROMK. On account of this property, apart from use as pharmaceutically active compounds in human medicine and veterinary medicine, they can also be employed as a scientific tool or as aid for biochemical investigations in which such an effect on ROMK is intended, and also for diagnostic purposes, for example in the in vitro diagnosis of cell samples or tissue samples. The compounds of Formula I can also be employed as intermediates for the preparation of other pharmaceutically active compounds.
- One or more additional pharmacologically active agents may be administered in combination with a compound of Formula I. An additional active agent (or agents) is intended to mean a pharmaceutically active agent (or agents) different from the compound of Formula I. Generally, any suitable additional active agent or agents, including but not limited to antihypertensive agents, anti-atherosclerotic agents such as a lipid modifying compound, antidiabetic agents and/or anti-obesity agents may be used in any combination with the compound of Formula I in a single dosage formulation (a fixed dose drug combination), or may be administered to the patient in one or more separate dosage formulations which allows for concurrent or sequential administration of the active agents (co-administration of the separate active agents). Examples of additional active agents which may be employed include but are not limited to angiotensin converting enzyme inhibitors (e.g, alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, moveltipril, perindopril, quinapril, ramipril, spirapril, temocapril, or trandolapril), angiotensin II receptor antagonists also known as angiotensis receptor blockers or ARBs (e.g., losartan i.e., COZAAR®, valsartan, candesartan, olmesartan, telmesartan and any of these drugs used in combination with hydrochlorothiazide such as HYZAAR®), neutral endopeptidase inhibitors (e.g., thiorphan and phosphoramidon), aldosterone antagonists, renin inhibitors (e.g. urea derivatives of di- and tripeptides (See
U.S. Pat. No. 5,116,835 ), amino acids and derivatives (U.S. Patents 5,095,119 and5,104,869 ), amino acid chains linked by non-peptidic bonds (U.S. Patent 5,114,937 ), di- and tripeptide derivatives (U.S. Patent 5,106,835 ), peptidyl amino diols (U.S. Patents 5,063,208 and4,845,079 ) and peptidyl beta-aminoacyl aminodiol carbamates (U.S. Patent 5,089,471 ); also, a variety of other peptide analogs as disclosed in the followingU.S. Patents 5,071,837 ;5,064,965 ;5,063,207 ;5,036,054 ;5,036,053 ;5,034,512 and4,894,437 , and small molecule renin inhibitors (including diol sulfonamides and sulfinyls (U.S. Patent 5,098,924 ), N-morpholino derivatives (U.S. Patent 5,055,466 ), N-heterocyclic alcohols (U.S. Patent 4,885,292 ) and pyrolimidazolones (U.S. Patent 5,075,451 ); also, pepstatin derivatives (U.S. Patent 4,980,283 ) and fluoro- and chloro-derivatives of statone-containing peptides (U.S. Patent 5,066,643 ), enalkrein, RO 42-5892, A 65317, CP 80794, ES 1005, ES 8891, SQ 34017, aliskiren (2(S),4(S),5(S),7(S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)-phenyl]-octanamid hemifumarate) SPP600, SPP630 and SPP635), endothelin receptor antagonists, vasodilators (e.g. nitroprusside), calcium channel blockers (e.g., amlodipine, nifedipine, veraparmil, diltiazem, gallopamil, niludipine, nimodipins, nicardipine), potassium channel activators (e.g., nicorandil, pinacidil, cromakalim, minoxidil, aprilkalim, loprazolam), diuretics (e.g., hydrochlorothiazide), sympatholitics, beta-adrenergic blocking drugs (e.g., propranolol, atenolol, bisoprolol, carvedilol, metoprolol, or metoprolol tartate), alpha adrenergic blocking drugs (e.g., doxazocin, prazocin or alpha methyldopa) central alpha adrenergic agonists, peripheral vasodilators (e.g. hydralazine), lipid lowering agents (e.g., HMG-CoA reductase inhibitors such as simvastatin, lovastatin, pravastatin, atorvastatin, pitavastatin and rosuvastatin, and cholesterol absorption inhibitors such as ezetimibe); niacin in immediate-release or controlled release forms, and particularly niacin in combination with a DP antagonist such as laropiprant (TREDAPTIVE®) and/or with an HMG-CoA reductase inhibitor; niacin receptor agonists such as acipimox and acifran, as well as niacin receptor partial agonists; metabolic altering agents including insulin sensitizing agents and related compounds for the treatment of diabetes such as biguanides (e.g., metformin), meglitinides (e.g., repaglinide, nateglinide), sulfonylureas (e.g., chlorpropamide, glimepiride, glipizide, glyburide, tolazamide, tolbutamide), thiazolidinediones also referred to as glitazones (e.g., pioglitazone, rosiglitazone), alpha glucosidase inhibitors (e.g., acarbose, miglitol), dipeptidyl peptidase inhibitors, e.g., (sitagliptin (JANUVIA®) and saxagliptin), ergot alkaloids (e.g., bromocriptine), combination medications such as JANUMET® (sitagliptin with metformin), and injectable diabetes medications such as exenatide and pramlintide acetate; or with other drugs beneficial for the prevention or the treatment of the above-mentioned diseases including but not limited to diazoxide. - Several methods for preparing the compounds of this invention are described in the following Schemes and Examples. Starting materials and intermediates are purchased, made from known procedures, or as otherwise illustrated. The Ar group shown in the below schemes can represent any of the substituted aromatic or substituted heterocyclic groups found in Z 1 or Z2 as defined previously.
- In general, synthesis of the covered compounds starts with alkylation of electrophile 1-1 (such as bromide, iodide, mesylatem or tosylate) with N-Boc protected piperazine (1-2) under basic conditions. The Boc protecting group (Greene, T.; Wuts, P. G. M. protective Groups in Organic Synthesis, John Wiley and Sons, Inc., New York, NY 1991) of 1-3 can be removed under acidic conditions, such as with TFA or HCl. The resulting piperazine 1-4 was alkylated for a second time with the corresponding electrophile (E) 1-5 to yield the product 1-6.
- Alternatively, the alkylation can be achieved under reductive amination conditions with the corresponding aldehyde or ketone using NaCNCH3 or Na(OAc)3BH (Scheme 2). Some compounds were made via a combination of the two alkylation methods, depending on whether the electrophile or aldehyde (ketone) is more easily accessible.
-
- Finally, intermediate 1-3 can also be prepared via a one pot ozonolysis - reductive amination method, when amine 4-1 is more easily accessible (Scheme 4). In this operation, tert-butyl diallylcarbamate 4-2 was first treated under ozonolysis conditions, which was followed by addition of amine 4-1, triethylamine, and Na(OAc)3BH. Further stirring of the reaction gave rise to intermediate 1-3. Removal of the Boc group gave rise to 1-4, which was further alkylated to furnish the final compound.
- Procedures for making compounds having bridged piperazines are described in the Examples.
- Reactions sensitive to moisture or air were performed under nitrogen or argon using anhydrous solvents and reagents. The progress of reactions was determined by either analytical thin layer chromatography (TLC) usually performed with E. Merck precoated TLC plates, silica gel 60F-254, layer thickness 0.25 mm or liquid chromatography-mass spectrometry (LC-MS). Typically the analytical LC-MS system used consisted of a Waters ZQ platform with electrospray ionization in positive ion detection mode with an Agilent 1100 series HPLC with autosampler. The column was usually a Water Xterra MS C18, 3.0 x 50 mm, 5 µm. The flow rate was 1 mL/min, and the injection volume was 10 µL. UV detection was in the range 210-400 nm. The mobile phase consisted of solvent A (water plus 0.06% TFA) and solvent B (acetonitrile plus 0.05% TFA) with a gradient of 100% solvent A for 0.7 min changing to 100% solvent B over 3.75 min, maintained for 1.1 min, then reverting to 100% solvent A over 0.2 min. Preparative HPLC purifications were usually performed using a mass spectrometry directed system. Usually they were performed on a Waters Chromatography Workstation configured with LC-MS System Consisting of: Waters ZQ single quad MS system with Electrospray Ionization, Waters 2525 Gradient Pump, Waters 2767 Injector / Collector, Waters 996 PDA Detetor, the MS Conditions of: 150-750 amu, Positive Electrospray, Collection Triggered by MS, and a Waters Sunfire C-18 5 micron, 30 mm (id) x 100 mm column. The mobile phases consisted of mixtures of acetonitrile (10-100%) in water containing 0.1%TFA. Flow rates were maintained at 50 mL/min, the injection volume was 1800 µL, and the UV detection range was 210-400 nm. Mobile phase gradients were optimized for the individual compounds. Reactions perfomed using microwave iradiation were normally carried out using an Emrys Optimizer manufactured by Personal Chemistry, or an Initiator manufactured by Biotage. Concentration of solutions was carried out on a rotary evaporator under reduced pressure. Flash chromatography was usually performed using a Biotage Flash Chromatography apparatus (Dyax Corp.) on silica gel (32-63 mM, 60 A pore size) in pre-packed cartridges of the size noted. 1H NMR spectra were acquired at 500 MHz spectrometers in CDCl3 solutions unless otherwise noted. Chemical shifts were reported in parts per million (ppm). Tetramethylsilane (TMS) was used as internal reference in CD3Cl solutions, and residual CH3OH peak or TMS was used as internal reference in CD3OD solutions. Coupling constants (J) were reported in hertz (Hz). Chiral analytical chromatography was performed on one of Chiralpak AS, Chiralpak AD, Chiralcel OD, Chiralcel IA, or Chiralcel OJ columns (250x4.6 mm) (Daicel Chemical Industries, Ltd.) with noted percentage of either ethanol in hexane (%Et/Hex) or isopropanol in heptane (%IPA/Hep) as isocratic solvent systems. Chiral preparative chromatography was conducted on one of Chiralpak AS, Chiralpak AD, Chiralcel OD, Ciralcel IA, or Chiralcel OJ columns (20x250 mm) (Daicel Chemical Industries, Ltd.) with desired isocratic solvent systems identified on chiral analytical chromatography or by supercritical fluid (SFC) conditions.
- Abbreviations used herein include: -C(O)CH3 (Ac); acetic acid (AcOH; HOAc); -OC(O)CH3 (OAc); aqueous (aq); benzyloxycarbonyl (Cbz); (dba) dibenzylideneacetone; tris(dibenzylidineacetone)dipalladium (Pd2(dba)3); N,N-diisopropylethylamine (DIPEA); N;N-dimethylformamide (DMF); dimethylsulfide (DMS); 1,1'-bis(diphenylphosphino)ferrocene (dppf , DPPF); ethyl acetate (EtOAc); diethyl ether (ether or Et2O); petroleum ether (PE); gram(s) (g); hexane (Hex); hour(s) (h or hr); hexamethylphosphoramide (HMPA); high pressure liquid chromatography (HPLC); 2-propanol (IPA); lithium diisopropylamide (LDA); mass spectrum (ms or MS); microliter(s) (µL); milligram(s) (mg); milliliter(s) (mL); millimole (mmol); minute(s) (min); methyl t-butylether (MTBE); medium pressure liquid chromatography (MPLC); N-methylmorpholine-N-oxide (NMO); phenyl (Ph); tetrakis(triphenylphosphine)palladium (Pd(PPh3)4); tris(dibenzylidineacetone)dipalladium (Pd2(dba)3); (benzotriazol-1-yloxy)tripyrrolidino-phosphonium hexafluorophosphate (PyBOP); retention time (Rt); room temperature (rt or RT); saturated aq sodium chloride solution (brine); triethylamine (TEA); trifluoroacetic acid (TFA); tetrahydrofuran (THF); flash chromatography (FC); liquid chromatography (LC); liquid chromatography-mass spectrometry (LCMS or LC-MS); supercritical fluid chromatography (SFC); t-butyloxycarbonyl (Boc or BOC); Diethylaminosulfur trifluoride (DAST); dichloromethane (DCM); dimethylacetamide (DMA; DMAC); dimethylsulfoxide (DMSO); 1,3-Bis(diphenylphosphino)propane (DPPP); acetic acid (HOAc); 3-chloroperoxybenzoic acid (m-CPBA); methyl (Me); methanol (MeOH); N-bromosuccinamide (NBS); thin layer chromatography (TLC).
- The following are representative procedures for the preparation of the compounds used in the following Examples, or which can be substituted for the compounds used in the following Examples which may not be commercially available.
-
- To a solution of N-Boc piperazine (2.8 g, 15 mmol) and 1-(2-bromoethyl)-4-nitrobenzene (3.5 g, 15 mmol) in DMF (75 mL) was added TEA (4.7 mL, 34 mmol) at RT. The mixture was heated to 60 °C for 16 hours. The crude mixture was diluted with EtOAc, washed with 0.1 N HCl and brine, dried over sodium sulfate, and concentrated. The product was precipitated by addition of hexane into a EtOAc solution. This solid was used in the bromination step without further purification. LC-MS (IE, m/z): 336 [M+ 1]+.
- The material obtained above was dissolved in dioxane, and treated with 4N HCl. LC showed complete conversion within 2 hours. The solvent was removed under reduced pressure, and the resulting solid was used without further purification. LC-MS (IE, m/z): 236 [M + 1]+.
-
- The 5-bromo-2 tetralone (2.0 g, 8.9 mmol), tetrakis(triphenylphosphine)palladium (0.62 g, 0.53 mmol) and zinc cyanide (0.73 g, 6.2 mmol) were added to 4 ml DMF in a 20 ml microwave tube. The mixture was degassed and microwaved at 80°C for 30 mins. TLC showed no starting material left and the mixture was diluted with ethyl acetate and washed with ammonium hydroxide (2M, x 4 ml). The organic layer was separated and dried over Na2SO4 then filtered. The solvent was evaporated under reduced pressure. The residue was chromatographed through 40 gm Isco Redi-sep column and eluted with 0-30% ethyl acetate- hexane to yield 6-oxo-5, 6, 7, 8-tetrahydronaphthalene-2-carbonitrile.
1H-NMR (500 MHz, CDCl3) δ ppm 7.57 (s,1H), 7.54 (d, J = 8.Hz, 1H), 7.26 (d, J = 8.Hz, 1H), 3.67(s, 2H), 3.14 (t, J = 6.7.Hz, 2H), 2.63 (t, J = 6.7.Hz, 2H). - Titanium (IV) isopropoxide (0.21 ml, 0.73 mmol), 6-oxo-5,6,7, 8-tetrahydronaphthalene-2-carbonitrile (100mg, 0.58 mmol), and tert-butyl piperazine-1-carboxylate(110 mg, 0.58 mmol) were stirred at room temperature. After 1 hour, ethanol (10 ml) and sodium cyanoborohydride (25.7 mg, 0.409 mmol) were added to the mixture and stirred for 16 hrs. LC-MS showed incomplete formation of product. More sodium cyanoborohydride (77 mg, 1.23 mmol) and 2 drops of HOAc were added and stirred overnight. The reaction was poured into sat'd NaHCO3 and extracted with ethyl acetate. The ethyl acetate layer was washed with brine then dried over MgSO4, filtered and evaporated to dryness. The residue was purified by prep-TLC plate using 50:50 EtOAc:Hexane solvent system.. Tert-butyl 4-(6-cyano-1, 2, 3,4-tetrahydronaphthalen-2-yl) piperazine-1-carboxylate was isolated. LC-MS (IE, m/z): 342 [M + 1]+, 1H-NMR (500 MHz, DMSO) δ ppm 7.54 (s,1H), 7.51 (d, J = 8.Hz, 1H), 7.21(d, J = 8.Hz, 1H), 3.31-3.28(m, 4H), 2.67-2.93(m, 5H), 2.46-2.62(m, 4H), 1.97 (b, 1H), 1.5-1.60 (m, 1H), 1.38 (s, 9H).
- Tert-butyl 4-(6-cyano-1,2, 3,4-tetrahydronaphthalen-2-yl) piperazine-1-carboxylate (110mg, 0.32 mmol) was stirred in trifluoroacetic acid (2 ml, 26.0 mmol) at RT overnight. The excess trifluoroacetic acid was then evaporated off under high vacuum. The resulting solid was used without further purification. LC-MS (IE, m/z): 242 [M + 1]+.
-
- A three-neck 5L round bottomed flask equipped with a stir bar, firestone valve, thermocouple, condenser and heating mantle was charged with tri-t-butyl phosphonium tetrafluoroborate (500 mg, 1.72 mmol), palladium (II) acetate (250 mg, 1.1 mmol) and 5-bromo-2-benzofuran-1(3H)-one (100 g, 470 mmol). DMF (1.88 L) was added to the flask, and the mixture was degassed three times by alternating vacuum and nitrogen purge. Commercially available bromo(1,3-dioxolan-2-ylmethyl)zinc solution (1.03 L, 516 mmol) was added via canula and the mixture was again degassed three times. The mixture was then heated at 85 °C for 5 h. Analysis by HPLC-MS indicated the reaction was not complete. The mixture was stirred at 85 °C for 5 more h. The mixture was then allowed to return to room temperature for overnight. 2-methylTHF (2L) and brine were added, and the mixture was stirred for 5 min. The layers were separated and the aqueous layer was extracted again with 2-methylTHF. The organic layers were combined, washed three times with brine (4L each), dried over MgSO4, filtered, and concentrated. The crude product was purified by flash chromatography (1.5 kg silica cartridge), eluting with 0-20% ethyl acetate in dichlromethane to afford 5-(1,3-dioxolan-2-ylmethyl)-2-benzofuran-1(3H)-one. LC-MS (IE, m/z); 221 [M+1]+.
- 5-(1,3-Dioxolan-2-ylmethyl)-2-benzofuran-1(3H)-one (61 g, 280 mmol) was combined with water (2.2 L) in a 5 L round bottomed flask equipped with a Claisen adapter, thermocouple, stir bar and nitrogen bubbler. Aqueous HCl solution (2M, 1.14 L, 2.29 mol) was added and the resulting mixture was heated at 40 °C for 8 h. Then the mixture was stirred overnight at room temperature. The mixture was extracted three times with 2 L of ethyl acetate. The combined organic layers were concentrated to give (1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde. LC-MS (IE, m/z): 177 (M+1)+.
-
- A 4-neck, 22-L, round bottom flask equipped with a mechanical stirrer, thermocouple, nitrogen bubbler, and condenser was charged with 5-bromophthalide (650 g, 3.0 mol), allyltri-n-butyltin (1200 g, 3.6 mol), tetrakis(triphenylphosphine)palladium (100 g, 0.089 mol), lithium chloride (250 g, 5.9 mol) and toluene (8.8 L). The mixture was evacuated and flushed with nitrogen 3 times and then was stirred at 100 °C for 4 hours. After slowly cooling to ambient temperature, the mixture was filtered and concentrated. The resulting solid was purified by silica gel column chromatography (heptane:ethyl acetate, 0->40%) to provide 5-allyl-2-benzofuran-1(3H)-one. 1H NMR (500 MHz, CD3OD) δ 7.83 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.33 (s, 1H), 5.98 (m, 1H), 5.29 (s, 2H), 5.11-5.18 (m, 2H), 3.52 (d, J = 8.2 Hz, 2H).
- 5-allyl-2-benzofuran-1(3H)-one (1.53 g, 8.78 mmol) was dissolved in methanol (30 mL). THF was added to solubilize the starting material. The resulting mixture was cooled in a dry ice acetone bath (-78 °C) and ozone was bubbled into the reaction until the color of the mixture changed to orange. Nitrogen was bubbled into the reaction for one minute to remove the excess ozone. Sodium borohydride (0.65 g, 2.9 mmol) was added at -78 °C, and the reaction mixture was allowed to warm to ambient temperature. The reaction mixture was concentrated part way and then taken up in ethyl acetate and water. The layers were separated and the organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to provide 5-(2-hydroxyethyl)-2-benzofuran-1(3H)-one. 1H NMR (500 MHz, CD3OD) δ 7.77 (m, 1H), 7.37-7.41 (m, 2H), 5.23 (s, 2H), 3.92 (m, 2H), 2.99 (m, 2H).
- To a solution of 5-(2-hydroxyethyl)-2-benzofuran-1(3H)-one (1.2 g, 6.8 mmol) in DCM at 0 °C was added carbon tetrabromide (2.3 g, 6.8 mmol), triphenylphosphine (1.8 g, 6.8 mmol), and imidazole (0.46 g, 6.8 mmol). The mixture was allowed to stir at 0 °C for 5 minutes, and then allowed to warm to RT and stir for 1.5 hours. The crude was concentrated and purified by silica gel chromatography (43% EtOAc with Hexanes). About 1.3 grams of 5-(2-Bromoethyl)-2-benzofuran-1(3H)-one was collected as a white solid. LC-MS (IE, m/z): 241/243 (M+1)+.
-
- A three neck 5 L round bottomed flask equipped with a nitrogen bubbler, thermocouple, and stirbar was charged with (1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (46.1 g, 262 mmol) and dichloromethane (1L). 1-Boc-piperazine (48.7 g, 262 mmol) in 1 L of dichloromethane was added and the mixture was stirred for 5 min. Sodium triacetoxyborohydride (111 g, 523 mmol) was added in portions at room temperature and the resulting mixture was stirred for 1 h. Water (1 L) was added and the mixture was stirred for 10 min. After gas evolution subsided the organic layer was separated and the aqueous layer was extracted with methylene chloride (1 L). The organic layers were combined, washed with brine, and concentrated. The crude product was purified by silica gel MPLC eluting with a 0-100% gradient of 5% methanol/DCM solution (Solvent A) to pure DCM (Solvent B) to afford 1,1-dimethylethyl-4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazine-1-carboxylate.
- To 1,1-dimethylethyl-4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazine-1-carboxylate (120 g, 347 mmol) in dioxane (800 mL) was added 4 N HCl in dioxane (87.0 mL, 347 mmol) and the resulting mixture was stirred at room temperature over night. The reaction mixture was concentrated and stored under vacuum overnight to afford 5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one hydrochloride. This can be used as is or converted to the free base by partitioning between an organic solvent and saturated NaHCO3 solution. LC-MS (IE, m/z): 247 (M+1)+.
-
- To a solution of 3-bromo-2-methyl benzoic acid (35 g, 163 mmol) in THF (200 mL) was added Borane THF Complex (1.0 M, 212 mL, 212 mmol). The mixture was allowed to stir for 24 h. TLC showed one single product spot. The reaction was quenched with water. The solvent THF was removed under reduced pressure. The resulting solid was dissolved in ethyl acetate (500 mL), washed with 1N HCl, sodium carbonate, and brine. The organic layer was dried over sodium sulfate and concentrated to afford (3-bromo-2-methylphenyl)methanol.
- To a flask charged with (3-bromo-2-methylphenyl)methanol (6.0 g, 30 mmol) was added a 1M TFA solution of Thallium Trifluoroacetate (16.2 g, 29.8 mmol). The mixture was stirred at RT overnight. Analysis by TLC showed no starting material remaining. The solvent was removed under vacuum, and the residue was pumped under high vacuum for 30 min to ensure complete removal of TFA. To the residue was then added Palladium(II) Chloride (529 mg, 2.98 mmol), Lithium Chloride (2.53 g, 59.7 mmol), Magnesium Oxide (2.41 g, 59.7 mmol), and MeOH (150 mL). The reaction was flushed with CO twice, and kept under CO at room temperature. Analysis by LC showed a big product spot within 2 hours. To this solution was added ethyl acetate to precipitate the salts. The black solution was filtered through a celite pad, washed with EtOAc, adsorbed onto silica and purified by silica gel chromatography to afford 5-bromo-4-methyl-2-benzofuran-1(3H)-one. 1H-NMR (500 MHz, CDCl3) δ ppm 7.71 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 5.25 (s, 2H), 2.37 (s, 3H).
- To a flask charged with 5-bromo-4-methyl-2-benzofuran-1(3H)-one (320 mg, 1.409 mmol) and a stir bar was added allyl tri-n-butyltin (0.655 ml, 2.11 mmol), Pd(PPh3)4 (244 mg, 0.211 mmol), lithium chloride (179 mg, 4.23 mmol), and toluene (15 mL). The reaction was purged with nitrogen 2 times then was heated at reflux for 4 hours. The product was separated by silica gel chromatography to give 4-methyl-5-prop-2-en-1-yl-2-benzofuran-1(3H)-one.
- A solution of the above olefin (220 mg, 1.2 mmol) in MeOH (20 mL) was cooled to -78 °C. To this solution was bubbled ozone until the reaction turned blue. Nitrogen was bubbled through the reaction to drive off excess ozone, followed by addition of DMS (0.870 mL, 11.7 mmol). The reaction was allowed to warm up to RT. The crude product was purified by flash chromatography to afford (4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde. 1H-NMR (500 MHz, CDCl3) δ ppm 9.78 (s, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.34 (d, J = 7.5 Hz, 1H), 5.27 (s, 2H), 3.90 (s, 2H), 2.23 (s, 3H).
- To a solution of (4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (160 mg, 0.84 mmol) and 1-Boc Piperazine (234 mg, 1.26 mmol) in MeOH (5 mL) was added NaCNBH3 (149 mg, 2.52 mmol) and a few drops of acetic acid. The reaction was allowed to stir at RT for 16 hours. TLC at that point showed good and complete reaction. The reaction was diluted with EtOAc (100 mL), washed with aq. NaHCO3 solution and brine, dried over Na2SO4, adsorbed onto silica gel, and purified by MPLC. 1,1-Dimethylethyl-4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazine-1-carboxylate was collected after removal of solvents.
- LC-MS: m/z 361 (M+1)+.
- 1,1-Dimethylethyl-4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazine-1-carboxylate (245 mg) was treated with 4N HCl in dioxane solution and the reaction was monitored until completion. The mixture was concentrated to afford 4-methyl-5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one hydrochloride. The hydrochloride can be converted to free base as needed by partitioning between organic solvent (EtOAc, DCM, or 30%IPA/CHCl3) and saturated Na2CO3 solution. 1H-NMR (500 MHz, DMSO) δ ppm 12.4 (broad, 1H), 9.80 (broad, 2H), 7.71 (d, J = 7.5 Hz, 1H), 5.53 (d, J = 7.5 Hz, 1H), 5.44 (s, 2H), 3.81 (m, 2H), 3.64-3.27 (m, 10H).
-
- A mixture of 5-bromo-4-methyl-2-benzofuran-1(3H)-one (980 mg, 4.3 mmol), allyl-tributyl-stannane (1.7 g, 5.2 mmol), LiCl (550 mg, 12.9 mmol) and Pd(PPh3)4 (0.1 g) in anhydrous toluene was stirred at reflux under N2 overnight. The solvent was removed under reduced pressure, and the residue was purified with silica gel column chromatography to give the product 4-methyl-5-prop-2-en-1-yl-2-benzofuran-1(3H)-one.
- To a stirred solution of 4-methyl-5-prop-2-en-1-yl-2-benzofuran-1(3H)-one (2.10 g, 11.2 mmol) in CCl4 (50 mL), acetonitrile (50 mL) and water (75 mL) was added sodium periodate (12 g, 55.8 mmol) and ruthenium oxide hydrate (210 mg) and the resulting mixture was stirred at ambient temperature overnight. The mixture was diluted with 100 mL DCM and 100 mL of water. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified with silica gel column chromatography to afford (4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetic acid.
- To a solution of (4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetic acid (100 mg, 0.48 mmol) in anhydrous DCM (10 mL) was added 1,1-dimethylethyl-N,N-bis(1-methylethyl)imidocarbamate (485 mg, 2.50 mmol) dropwise at 0 °C under N2. Then the mixture was stirred at r.t. over night. The mixture was filtered and the filtrate was washed with 2N HCl and brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative TLC to give 1,1-dimethylethyl (4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetate. 1H-NMR (400 MHz, CDCl3) δ ppm 7.70(d, J=7.8 Hz, 1H), 7.38 (d, J=7.0 Hz, 1H), 5.25 (s, 2H), 3.67 (s, 3H), 2.27 (s, 3H), 1.44 (s, 9H).
- A solution of 1,1-dimethylethyl (4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetate (770 mg, 3.1 mmol) in 30 mL of anhydrous THF was cooled to -78 °C. NaHMDS (4.0 mmol) was added to the reaction dropwise at -78 °C. After the addition, the mixture was stirred at -78 °C for 1 h and then CH3I (462 mg, 3.20 mmol) was added dropwise at -78 °C. The reaction was warmed to room temperature slowly and stirred at ambient temperature over night. The reaction was quenched with NH4Cl solution, and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified via preparative TLC to afford 1,1-dimethylethyl-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)propanoate. 1H-NMR (400 MHz, CDCl3) δ ppm 7.67(d, J=7.8 Hz, 1H), 7.37 (d, J=7.8 Hz, 1H), 5.19 (s, 2H), 3.80(dd, J=7.0 Hz, 1H), 2.24 (s, 3H), 1.40 (d, J=7.0 Hz, 1H), 1.32 (s, 9H).
- To a solution of 1,1-dimethylethyl-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)propanoate (400 mg, 1.4 mmol) in 10 mL of anhydrous DCM was added TFA (2.5 mL) dropwise at r.t. Then the mixture was stirred for 1 hour. The solvent was removed under vacuum to give the crude 2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)propanoic acid, which was used for next step without purification.
- To a solution of 2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)propanoic acid (300 mg, 1.4 mmol) in 18 mL of anhydrous THF was added BH3.THF (2 mL, 2 mmol) dropwise at 0 °C. Then the mixture was warmed to room temperature slowly and then stirred for 3 hours. Then the mixture was quenched with MeOH and the solvent was removed under vacuum. The residue was the purified via prep-TLC to give 5-(2-hydroxy-1-methylethyl)-4-methyl-2-benzofuran-1(3H)-one. 1H-NMR (400 MHz, CDCl3) δ ppm 7.73(d, J=7.8 Hz, 1H), 7.40 (d, J=7.8 Hz, 1H), 5.23 (s, 2H), 3.77(d, J=7.0 Hz, 2H), 3.36~3.42 (m, 1H), 2.30 (s, 3H), 1.27 (d, J=7.0 Hz, 3H).
- 5-(2-Hydroxy-1-methylethyl)-4-methyl-2-benzofuran-1(3H)-one (161 mg, 0.781 mmol, 1.0 eq) was dissolved in DCM (6 ml). To above solution was added Dess-MartinPeriodinane (397 mg, 0.937 mmol, 1.2 eq). The reaction was stirred at rt for 2 hr. To the reaction was added DCM (10 Ml), Na2S2O3 (6 mL) and H2O (6 mL). The mixture was stirred at r.t. for 30 minutes and formed two layers. The bottom layer was separated and washed with aqueous NaHCO3, brine and water, dried over Na2SO4, filtered, and concentrated to dryness. The crude product was used to next step without purification. 1H NMR (500 MHz, CDCl3, δ in ppm): 9.70 (1H, s, CHO), 7.79 (1H, d, J = 7.8 Hz), 7.28 (1H, d, J= 7.8 Hz), 5.28 (2H, s), 3.27 (1H, m), 2.32 (3H, s), 1.50 (3H, d, J= 7.2 Hz).
-
- In a 100 mL round bottom flask, 2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)propanal (100 mg, 0.49 mmol, 1.0 eq) and N-Boc Piperazine (91 mg, 0.49 mmol, 1.0 eq) was dissolved in DCM (10 mL). To above solution was added sodium triacetoxyborohydride (208 mg, 0.98 mmol, 2.0 eq). The reaction was stirred at RT for 16 hr. The reaction was then diluted with DCM (10 mL), washed with aqueous bicarbonate, water and brine. The organic phase was dried over MgSO4, filtered and concentrated. The product was obtained after purification by flash column chromatography (5% MeOH/DCM). LC-MS (IE, m/z): 375.4 [M + 1]+.
- tert-Butyl-4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)propyl]piperazine-1-carboxylate (160 mg, 0.43 mmol) was stirred in TFA (3 mL) at r.t for 3 hr. The reaction was concentrated and pump over high vacuum pump overnight to give the desired product, which could be converted to its freebase by partitioning between an organic solvent and saturated NaHCO3 solution. LC-MS (IE, m/z): 275 [M+ 1]+.
-
- A solution of diisopropylamine (13 ml, 93 mmol)) in THF (155 ml) at -78 °C was treated with n-BuLi (1.6M in Hexanes; 58 ml, 93 mmol) over a period of 15 minutes using a syringe pump. In a separate flask, a solution of 2-methyl-4-bromo benzoic acid (10 g, 46 mmol) and HMPA (8.3 ml, 46 mmol) in THF (155 ml) was cooled to -78 °C. Methyl Lithium (29 ml, 46 mmol) was added slowly via syringe to the cooled solution in order to make the lithio carboxylate. The resulting solution was stirred for 10 minutes and then transferred via cannula to the LDA solution at -78 °C. The resulting bright red solution was stirred at -78°C for an additional 1 hour before being quenched with anhydrous acetaldehyde (7.9 ml, 140 mmol) (color changed from red to orange to clear yellow) and the reaction was then taken out of the dry ice acetone bath and allowed to stir for an additional 1 hour. The flask containing the reaction mixture was then resubmerged in the dry ice acetone bath before it was quenched with 4M HCl in Dioxane (50mL) followed by 25mL of MeOH. The reaction was stirred at room temp for an additional 1 hour. The crude reaction was partitioned b/w 200mL EtOAc and 200mL water. The organic layer was washed with waster, brine, dried with mag. sulfate, filtered and concentrated. Purification via MPLC (30-70% DCM/Hexanes) afforded 9.4g (84% yield) of 6-bromo-3-methyl-3,4-dihydro-1H-isochromen-1-one as an off white solid. 1H NMR (500 MHz; CDCl3): 7.98 (d, J = 8.2 Hz, 1H), 7.56 (dd, J = 1.5, 8.2 Hz, 1H), 7.45 (s, 1H), 4.71 (m, 1H), 2.94 (m, 2H), 1.55 (d, J = 6.3 Hz, 3H). LC-MS (IE, m/z): 241 [M+1]+.
- A sealed tube was charged with aryl bromide, palladium(II) acetate (0.028 g, 0.12 mmol) and tri-t-butylphosphine-BF4 complex (0.072 g, 0.249 mmol) and sealed. The tube was evacuated and refilled with nitrogen before DMF (12 ml) and 6-bromo-3-methyl-3,4-dihydro-1H-isochromen-1-one (0.75 g, 3.1 mmol) were added followed by bromo(1,3-dioxolan-2-ylmethyl)zine (6.2 ml, 3.1 mmol). The tube was heated to 110 °C in the microwave for 75 minutes, after which it was cooled, diluted with EtOAc, filtered, concentrated and purified via MPLC (20-50% EtOAc/Hexanes) to afford 490mg (64% yield) of 6-(1,3-dioxolan-2-ylmethyl)-3-methyl-3,4-dihydro-1H-isochromen-1-one (Compound 1B) as a clear oil which solidifies on standing. 1H NMR (500 MHz; CDCl3): 8.04 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.17 (s, 1H), 5.11 (t, J=4.7 Hz, 1H), 4.68 (m, 1H), 3.96 (m, 2H), 3.88 (m, 2H), 3.03 (d, J= 4.9 Hz, 2H), 2.93 (m, 2H), 1.54 (d, J = 6.4 Hz, 3H). LC-MS (IE, m/z): 249 [M+1]+.
- A 1:1 solution of dioxane : 3N HCl was added to a flask containing of 780 mg( 3.2 mmol) of 6-(1,3-dioxolan-2-ylmethyl)-3-methyl-3,4-dihydro-1H-isochromen-1-one. The reaction was then stirred at room temp overnight. The crude reaction mixture was then partitioned between water and DCM. The organic layer was washed with saturated sodium bicarbonate solution, followed by brine. The organic layer was then dried with magesium sulfate, filtered and concentrated. The crude aldehyde was redissolved in DCM. To the solution was added boc-piperazine (671 mg, 3.6 mmol) followed by sodium triacetoxyborohydride (1.9 g, 9.0 mmol). the reaction mixture was allowed to stir overnight before being quenched with 10mL of MeOH. The excess solvent was removed and the residue was re-redissolved in DCM; washed with water and brine, dried with magnesium sulfate, filtered,concentrated and purified via MPLC (50-100% EtOAc/Hex) to afford 850 mg of tert-butyl 4-[2-(3-methyl-1-oxo-3,4-dihydro-1H-isochromen-6-yl)ethyl]piperazine-1-carboxylate as a golden oil. 1H NMR (500 MHz; CDCl3): 8.02 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 7.7 Hz, 1H), 7.09 (s, 1H), 4.68 (m, 1H), 3.49 (m, 4H), 2.94 (m, 4H), 2.88 (m, 2H), 2.51 (m, 4H), 1.54 (d, J= 6.8 Hz, 3H), 1.48 (s, 9H). LC-MS (IE, m/z): 375 [M+1]+.
- A solution of tert-butyl 4-[2-(3-methyl-1-oxo-3,4-dihydro-1H-isochromen-6-yl)ethyl]piperazine-1-carboxylate (850 mg, 2.3 mmol) was stirred in 4N HCl in Dioxane for 4 hours. The excess solvent was then removed to give the free amine as the HCl salt. LC-MS (IE, m/z): 275 [M+1]+.
-
- Chiral separation of racemic 6-bromo-3-methyl-3,4-dihydro-1H-isochzomen-1-one using ChiralPak AS 4.6x250mm 10u column, eluting with 60% IPA/Heptane. The faster eluting isomer was identified as the S-isomer. 1H NMR (500 MHz, CDCl3): 7.98 (d, J = 8.2 Hz, 1H), 7.56 (dd, J = 1.5, 8.2 Hz, 1H), 7.45 (s, 1H), 4.71 (m, 1H), 2.94 (m, 2H), 1.55 (d, J = 6.3 Hz, 3H). LC-MS (IE, m/z): 241 [M+1]+.
- (3S)-6-(1,3-dioxolan-2-ylmethyl)-3-methyl-3,4-dihydro-1H-isochromen-1-one was obtained using the procedure described for the synthesis of 6-(1,3-dioxolan-2-ylmethyl)-3-methyl-3,4-dihydro-1H-isochromen-1-one utilizing the chiral S-enantiomer as the starting material. 1H NMR (500 MHz, CDCl3): 8.04 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.17 (s, 1H), 5.11 (t, J=4.7 Hz, 1H), 4.68 (m, 1H), 3.96 (m, 2H), 3.88 (m, 2H), 3.03 (d, J= 4.9 Hz, 2H), 2.93 (m, 2H), 1.54 (d, J = 6.4 Hz, 3H). LC-MS (IE, m/z): 249 [M+1]+.
- tert-Butyl 4-{2-[(3S)-3-methyl-1-oxo-3,4-dihydro-1H-isochromen-6-yl]ethyl}piperazine-1-carboxylate was obtained using the procedure described for the synthesis of tert-butyl 4-{2-[3-methyl-1-oxo-3,4-dihydro-1H-isochromen-6-yl]ethyl}piperazine-1-carboxylate utilizing the chiral S-enantiomer as the starting material in the reaction. 1H NMR (500 MHz, CDCl3): 8.02 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 7.7 Hz, 1H), 7.09 (s, 1H), 4.68 (m, 1H), 3.49 (m, 4H), 2.94 (m, 4H), 2.88 (m, 2H), 2.51 (m, 4H), 1.54 (d, J= 6.8 Hz, 3H), 1.48 (s, 9H). LC-MS (IE, m/z): 375 [M+1]+.
- A solution of tert-butyl 4-{2-[(3S)-3-methyl-1-oxo-3,4-dihydro-1H-isochromen-6-yl]ethyl}piperazine-1-carboxylate in 4N HCl indioxane was stirred at room temp for 4 hours and the excess solvent removed. The residue was partitioned between 10% IPA/Chloroform and 1N NaOH. The organic layer was dried over magnesium sulfate, filtered and concentrated. The free amine was used without further purification.
-
- 5-Bromo-2,1,3-benzoxadiazole (10 g, 50.3 mmol) was dissolved in toluene (300 ml) and added Lithium chloride (6.4 g, 150 mmol), Pd(Ph3P)4 (2.90 g, 2.50 mmol), and allyl tributyltin (19 ml, 60 mmol). The reaction mixture was degassed and refluxed under N2 for 3 hrs. It was cooled and poured into water then extracted with ethyl acetate. The organic layer was washed with brine 1x, dried and evaporated to dryness. The residue was chromatographed through 120g ISCO Redi-Sep columns and eluted with 0-10% ethyl acetate / hexane to yield 5-allyl-2,1,3-benzoxadiazole. 1H-NMR (500 MHz, DMSO): δ ppm 7.96 (d, J=9.1 Hz, 1H), 7.44(d, J= 9.1 Hz, 2H), 5.95-6.04 (m, 1H), 5.17 (d, J=14.7Hz, 1H), 5.15 (d, J=8.9Hz, 1H), 3.50 (d, J= 6.7Hz, 2H)
- To a solution of 5-allyl-2,1,3-benzoxadiazole (480 mg, 3.0 mmol) in DCM was cooled to -78 °C. Ozone was bubbled in until a bluish tint then bubbled in nitrogen to get rid of excess ozone. The Boc- piperazine (560 mg, 3.0 mmol) was then added followed by sodium triacetoxyborohydride (2500 mg, 12 mmol). The reaction mixture was warmed up to RT and stirred overnight. Poured the reaction into 1 N NaOH and extracted with ethyl acetate 2X. The ethyl acetate layer was dried over MgSO4, filtered and evaporated to dryness. The residue was purified through a 40 g Redi-sep column to yield tert-butyl 4-[2-(2,1,3-benzoxadiazol-5-yl)ethyl]piperazine-1-carboxylate. tert-Butyl 4-[2-(2,1,3-benzoxadiazol-5-yl)ethyl]piperazine-1-carboxylate (470 mg, 1.4 mmol) was then dissolved in dioxane (10 mL) and added 7 mL of 4M HCl in dioxane. The reaction was stirred at room temperature overnight. Evaporated off all solvent and the residue was taken up in ethyl acetate basified with 1N NaOH. The ethyl acetate was separated and washed with brine then dried over Na2SO4 and evaporated to dryness. The residue was purified by chromatography using 5% (NH4OH:MeOH 1:10) in 95% DCM to yield 5-(2-piperazin-1-ylethyl)-2,1,3-benzoxadiazole. 1H-NMR (600 MHz,CDCl3): δ 7.72(d, J = 9.2Hz, 1H), 7.28 (d, J = 9.2Hz, 1H), 2.92( t, J = 4.9 Hz, 2H), 2.88 (t, J = 7.6Hz, 1H), 2.65 (t, J = 7.6Hz, 1H). LC-MS: M+1= 233.
-
- To a solution of 5-nitro-indene-2-one (1.0 g, 5.6 mmol) in methanol (40 mL) containing a stir bar was added sodium cyanoborohydride (1.7 g, 28 mmol) and N-Boc piperazine (1.6 g, 8.5 mmol) followed by addition of few drops of acetic acid; the resulting mixture was stirred for overnight. Analysis of the reaction mixture by LC indicated that reaction had gone to completion. The solution was concentrated in vacuo and the resulting crude was dissolved in EtOAc and washed with saturated sodium bicarbonate solution, and brine, then dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was then subjected for purification by silica gel column chromatography (5% MeOH in DCM) to provide tert-butyl 4-(5-nitro-2, 3-dihydro-1H-inden-2-yl) piperazine-1-carboxylate. LC-MS (IE, m/z): 348 [M+1]+. The material was further treated with TFA to remove the Boc group. Removal of volatiles gave rise to 1-(5-nitro-2,3-dihydro-1H -inden-2-yl)piperazine, which was used without further purification.
-
- In a 100 mL round bottom flask, tert-butyl di(prop-2-en-1-yl)carbamate (0.74 mL, 3.4 mmol) was dissolved in dichloromethane (10 mL). The solution was cooled to -78 °C. To above solution was bubbled ozone for 15 min. The solution turned into light blue and the color stayed. To above solution was bubbled nitrogen to remove excess ozone until the solution turned into colorless. To above solution was added (5-bromo-2,3-dihydro-1H-inden-2-amine (1.0 g, 3.4 mmol), triethylamine (0.48 mL, 3.4 mmol) followed by sodium triacetoxyborohydride (4.3 g, 20 mmol). The reaction was allowed to warm up to room temperature and stirred at this temperature overnight. HPLC-MS showed product was formed as major peak. To above solution was added water (5 mL), extracted with dichloromethane (10 mL x 3). The organic phase was dried over MgSO4, filtered and concentrated. The product was obtained as white solid after purification by flash column chromatography. LC-MS (IE, m/z): 381.2 [M + 1]+. 1H NMR (500 MHz, CDCl3, δ in ppm): 7.30 (1H, s), 7.25 (d, J= 8.0 Hz, 1H), 7.03 (d, J= 8.0 Hz, 1H), 2.0 -4.0 (m, 13H), 1.5 (s, 9H).
- To a 5 mL microwave vial was charged with tert-butyl 4-(5-bromo-2,3-dihydro-1H-inden-2-yl)piperazine-1-carboxylate (370 mg, 0.97 mmol), zinc cyanide (114 mg, 0.97 mmol) and palladium triphenylphosphane (1:4) (56 mg, 0.049 mmol). Above mixture was dissolved in N-methyl-2-pyrrolidinone (1 mL). The reaction vial was degassed, filled with N2 and heated in microwave reactor at 85 °C for 2 hr, then at 100 °C for 20 min. To above reaction was added dichloromethane (5 mL), washed with small amount of water. The organic phase was dried over MgSO4, filtered and concentrated. The product was obtained as white solid after purification by flash column chromatography. LC-MS (IE, m/z): 328.3 [M + 1]+. 1H NMR (500 MHz, CDCl3, δ in ppm): 7.47 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 2.4 - 3.6 (m, 13H), 1.5 (s, 9H).
- In a 4 mL reaction vial, was added tert-butyl 4-(5-cyano-2,3-dihydro-1H-inden-2-yl)piperazine-1-carboxylate. To above vial was added 4 N HCl in dioxane (1 mL), let stirred at RT for 2 hr. The reaction mixture was concentrated to give the desired product. LC-MS (IE, m/z): 228.3 [M + 1]+.
-
- A solution of phthalic anhydride (1.2 g, 8.3 mmol) and (3-aminophenyl)acetic acid (1.0 g, 6.9 mmol) in acetic acid (25 mL) was heated to reflux for 16 hours. The reaction was cooled, and diluted with 25 mL of EtOAc. A lot of solids crashed out from the solution. The solids were collected by filtration, and identified as the desired [3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]acetic acid. LC-MS (IE, m/z): 282 [M+ 1]+.
- To a solution of [3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]acetic acid (0.75g, 2.7 mmol) in DCM (25 mL) was added oxalyl chloride (0.28 mL, 3.2 mmol) and a drop of DMF. The mixture was allowed to stir at RT until all solids disappeared. At that point, the solution was cooled to to 0 °C with an ice bath, and aluminum chloride (1.1g, 8.0 mmol) was added into the reaction slowly. After stirring the mixture for another 10 minutes, ethylene was bubbled through the reaction via a long needle. TLC showed complete reaction within 30 minutes. The reaction was poured into ice water, neutralized with sodium carbonate, extracted with DCM, dried, concentrated, and purified by MPLC (Hexane/EtOAc). LC-MS (IE, m/z): 292 [M + 1]+.
- To a flask charged with 2-(7-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-1H-isoindole-1,3(2H)-dione (0.25g, 0.86 mmol), N-Boc piperazine (0.24g, 1.3 mmol), and a stir bar was added titanium isopropoxide (2.5 mL), ethanol (10 mL), and sodium cyanoborohydride (0.27g, 4.3 mmol). The mixture was allowed to stir at RT for 2 hours. LC showed formation of the desired product at that point. The reaction was diluted with EtOAc (50 mL), washed with water and brine, dried over sodium sulfate, filtered and concentrated, and purified by MPLC to afford the desired product. LC-MS (IE, m/z): 462 [M + 1]+.
- To a flask charged with tert-butyl 4-[7-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl]piperazine-1-carboxylate (300mg, 0.65 mmol) and a stir bar was added TFA (2 mL). The mixture was allowed to stir at RT for 1 hour. LC showed complete removal of the Boc group. TFA was removed under reduced pressure, and the residue was dissolved in DCM (5 mL). To the solution was added pyridine and trifluoroacetic anhydride (0.27 mL, 2.0 mmol). LC showed formation of the desired product within 30 minutes. The product was purified by MPLC.
- To a solution of 2-{7-[4-(Trifluoroacetyl)piperazin-1-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}-1H-isoindole-1,3(2H)-dione (35mg, 0.77 mmol) in conc. H2SO4 (2 mL) was added potassium nitrate (15 mg, 0.15 mmol) at 0 °C. LC showed formation of the desired product within 10 minutes. The reaction was poured into ice, and extracted with DCM twice. The product was purified by mass-directed HPLC. LC-MS (IE, m/z): 503 [M + 1]+.
- To a solution of 2-{3-Nitro-7-[4-(trifluoroacetyl)piperazin-1-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}-1H-isoindole-1,3(2H)-dione (150 mg, 0.30 mmol) in Ethanol (5 mL) was added hydrazine (0.094 mL, 3.0 mmol). The solution turned bright yellow right away. LC showed cleavage of the phthalic anhydride as well as the trifluoroacetate group. Boc anhydride (65 mg, 0.30 mmol) and aqueous sodium bicarbonate (5 mL) were added to the reaction. LC showed formation of the product within 15 minutes. The reaction was diluted with water (20 mL), extracted with DCM twice, dried over sodium sulfate, and purified by MPLC (hexane/EtOAc). LC-MS (IE, m/z): 377 [M + 1]+.
- To a solution of tert-Butyl 4-(7-amino-6-nitro-1,2,3,4-tetrahydronaphthalen-2-yl)piperazine-1-carboxylate (160 mg, 0.42 mmol) in ethanol (3 mL) was added potassium hydroxide (36 mg, 0.64 mmol). The solution was stirred until all solids dissolved. At that point, sodium hypochlorite (1.3 mL, 1.3 mmol) was dropped into the reaction. LC showed quite slow reaction. Another 1.3 mL of sodium hypochlorite was added to complete the reaction. The desired product was separated by reverse phase HPLC (water: Acetonitrile with 0.1% TFA). LC-MS (IE, m/z): 375 [M + 1]+.
- A solution of tert-Butyl 4-(1-oxido-5,6,7,8-tetrahydronaphtho[2,3-c][1,2,5]oxadiazol-6-yl)piperazine-1-carboxylate (100 mg, 0.27 mmol) and triphenyl phosphine (140 mg, 0.53 mmol) in THF (3mL) was heated to 140 °C in a microwave reactor for 30 minutes. LC showed formation of the desired product, which was separated by reverse phase HPLC (water: Acetonitrile with 0.1% TFA). LC-MS (IE, m/z): 359 [M+ 1]+.
- To a flask charged with tert-Butyl-4-(5,6,7,8-tetrahydronaphtho[2,3-c][1,2,5]oxadiazol-6-yl)piperazine-1-carboxylate (50 mg, 0.14 mmol) was added 4N HCl in dioxane (1mL). The mixture was allowed to stir for 30 minutes at RT. LC showed complete reaction. The solvent was removed under reduced pressure, and the resulting 6-Piperazin-1-yl-5,6,7,8-tetrahydronaphtho[2,3-c][1,2,5]oxadiazole hydrochloride was used without further purification. LC-MS (IE, m/z): 259 [M + 1]+.
-
- To a 20 mL microwave tube was added 2-bromo-5-nitropyridine (0.20 g, 0.98 mmol), potassium vinyltrifluoroborate (145 mg, 1.1 mmol), PdCl2(dppf)-CH2Cl2 complex (40 mg, 0.049 mmol), and a stir bar. The tube was sealed, and ethanol (6 mL) and triethylamine (0.41 mL, 3.0 mmol) was added via syringe. The mixture was purged three times with nitrogen and then heated to 120 °C for 30 minutes. LC at that point showed mostly product. The reaction was diluted with DCM, adsorbed onto silica gel, and purified by silica gel flash chromatography (Hexane:EtOAc). LC-MS (IE, m/z): 151 [M + 1]+.
- To a flask charged with 5-nitro-2-vinylpyridine (55 mg, 0.37 mmol), N-Boc Piperazine (68 mg, 0.37 mmol), and a stir bar was added dioxane (0.6 mL). The flask was sealed and purged with nitrogen. To the flask was injected a stock solution of 250 mg Ru(COD)(methyallyl)2 and 481 mg 1,3-Bis(diphenylphosphino)propane in 3.2 mL dioxane (0.4 mL) and trifluoromethanesulfonic acid (3.2 uL, 0.037 mmol). The mixture was heated to 100 °C for 16 hours. LC showed formation of the desired product, which was separated by silica gel flash chromatography (Hexane:EtOAc). LC-MS (IE, m/z): 337 [M + 1]+. The material was further treated with 4N HCl in dioxane, and the crude 1-[2-(6-nitropyridin-3-yl)ethyl]piperazine hydrochloride was carried on without further purification. LC-MS (IE, m/z): 237 [M + 1]+.
-
- A solution of tert-butyl 3-methylpiperazine-1-carboxylate (100 mg, 0.50 mmol), 1-(2-bromoethyl)-4-nitrobenzene (170 mg, 0.75 mmol), tetrabutylammonium iodide (18 mg, 0.05 mmol), K2CO3 (138 mg, 1.0 mmol), and DMF (2 mL) was heated to 80 degrees for 16 hours. LC showed formation of the desired product. The reaction was diluted with EtOAc (50 mL), washed with aq. LiCl, dried over sodium sulfate, concentrated and purified by MPLC (Hexane: EtOAc). The product was further treated with 4N HCl in dioxane to furnish the piperazine as the HCl salt LC-MS (IE, m/z): 250 (M+1)+. INTERMEDIATE 16
- To a solution of [4-(1H-tetrazol-1-yl)phenyl]acetic acid (0.50g, 2.4 mmol) in DCM (10 mL) was added oxalyl chloride (0.37g, 2.9 mmol) and a drop of DMF. The mixture was allowed to stir at RT for 2 hours. The solvent was removed under reduced pressure, and the residue was redissolved in DCM. The solution was cooled to 0 °C with an ice bath. To this solution was added aluminum chloride (0.98g, 7.4 mmol) in small portions. Ethylene was then bubbled into the reaction via a long needle for 2 hours. LC showed formation of the desired product. The reaction was poured into ice and extracted with DCM. The extractions were combined, dried over sodium sulfate, adsorbed onto silica gel, and purified by MPLC (Hexane/EtOAc). The desired 6-(1H-tetrazol-1-yl)-3,4-dihydronaphthalen-2(1H)-one was collected as a off-white solid. LC-MS (IE, m/z): 215 [M + 1]+.
-
- Lithium chloride (0.64 g, 15.1 mmol) was added to a mixture of 5-bromo-2,1,3-benzoxadiazole (1.0 g, 5.0 mmol), tetrakis(triphenylphosphine)palladium (0.29 g, 0.25 mmol) and allyl tri-n-butyltin (1.87 ml, 6.0 mmol) in 30 ml toluene then refluxed for 3 hours. The reaction was filtered, concentrated, and loaded into an ISCO 120 gm Redi-Sep then eluted with a gradient of 0-50% ethyl acetate/hexane. 1H-NMR (500 MHz, CDCl3) δ ppm 7.76 (d, J=9 Hz, 1H), 7.59 (s,1H ), 7.28( d, J = 9Hz, 1H), 5.95-6.03 (m, 1H), 5.24 (d, J = 10 Hz, 1H), 5.20 (d, J = 15 Hz, 1H), 3.49 (d, J = 6.5Hz, 2H).
- A solution of 5-allyl-2,1,3-benzoxadiazole (500 mg, 3.1 mmol) in DCM (10 ml) was cooled to - 78 °C then bubbled in ozone until a faint blue color occurred. The reaction was purged with nitrogen to get rid of excess ozone then added dimethyl sulfide (2.3 ml, 31 mmol) and stirred at room temperature for 2 hours. The reaction was concentrated and used without further purification.
-
- To a solution of 4-bromo-2,3-dihydro-1H-inden-1-one (1.00 g, 4.74 mmol) in 5 mL of DMF was added Zn(CN)2 (556 mg, 4.74 mmol) and Pd(PPh3)4 (77 mg, 0.14 mmol), and the reaction mixture was stirred under microwave irradiation for 1 h at 165 °C. The solvent was removed in vacuum to afford the crude compound, which was purified via column chromatography to afford 1-oxo-2,3-dihydro-1H-indene-4-carbonitrile.
- Sodium bis(trimethylsilyl)amide (2 mL, 4 mmol, 2M in THF) was added to a stirred suspension of (methoxy methyl)triphenylphosphonium chloride (1.47 g, 4.29 mmol) in dry THF (20 mL) at 0 °C for 35 min and a solution of 1-oxo-2,3-dihydro-1H-indene-4-carbonitrile (450 mg, 2.86 mmol) in THF (10 mL) added over 10 min. The mixture was stirred at 0 °C for 2 h and at room temperature for 1 h. Water was added and the mixture was partitioned between EtOAc and brine. The organic layer was dried and concentrated. The crude product was purified via prep-TLC (PE:EtOAc=10:1) to afford (1E)-1-[(methyloxy)methylidene]-2,3-dihydro-1H-indene-4-carbonitrile. 1H-NMR (400 MHz, CDCl3) δ ppm 8.00 (d, J=8.3 Hz, 0.4H), 7.42 (d, J=8.3 Hz, 0.6H), 7.30-7.40 (m, 1H), 7.18-7.22 (m, 1H), 6.70 (s, 0.6H), 6.22 (s, 0.4H), 3.72 (s, 3H), 3.15 (t, J=5.7 Hz, 2H), 2.70-2.82 (m, 2H).
- A solution of (1E)-1-[(methyloxy)methylidene]-2,3-dihydro-1H-indene-4-carbonitrile (250 mg, 1.05 mmol) in DCM (5 mL) was added BBr3 dropwise at -78 °C under N2. Then the mixture was stirred at this temperature for 3h. It was poured into ice-saturated NaHCO3 solution, and extracted with DCM. The organic layer was washed with brine and dried over Na2SO4. The solvent was removed in vacuo to give crude 1-formyl-2,3-dihydro-1H-indene-4-carbonitrile (150mg, crude), which is used for next step directly. 1H-NMR (400 MHz, CDCl3) δ ppm 9.72 (s, 1H), 7.54 (d, J=7.6 Hz, 2H), 7.34 (t, J=7.6 Hz, 1H), 3.76 (s, 1H), 3.18-3.24 (m, 2H), 2.42-2.58 (m, 2H).
- 1-Formyl-2,3-dihydro-1H-indene-4-carbonitrile (0.22 g, 1.3 mmol) was dissolved in MeOH (8 mL) and treated with tert-butyl piperazine-1-carboxylate (0.35 g, 1.9 mmol) followed by treatment of sodium cyanoborohydride (0.40 g, 6.43 mmol) and few drops of Acetic acid. The resulting mixture was then stirred at room temperature overnight. LC indicated completion of the reaction. The reaction mixture was concentrated in vacuo, treated with EtOAc and washed with saturated NaHCO3, dried with Na2SO4, filtered and loaded into MPLC for separation over silica gel. with 10% MeOH in DCM to afford tert-butyl 4-[(4-cyano-2,3-dihydro-1H-inden-1-yl)methyl]piperazine-1-carboxylate. This material was further treated with TFA to remove the Boc group. Removal of volatiles gave rise to 1-(piperazin-1-ylmethyl)indane-4-carbonitrile, which was used as the crude. LC-MS (IE, m/z): 242 (M+1)+.
-
- To a 50 mL flask containing a stir bar were added 2-methoxy-4-bromobenzonitrile (0.30 g, 1.4 mmol), tetrakis(triphenylphosphine)palladium (82 mg, 0.071 mmol), allyltri-n-butyltin (0.88 mL, 2.8 mmol), and lithium chloride (0.120 g, 2.83 mmol). The resulting mixture was then dissolved in anhydrous toluene (16 mL); the flask was placed in an oil bath and heated at 130 °C. LC as well as TLC (hexanes/EtOAc =1/0.3) indicated that reaction had gone to completion. The flask was taken out of the oil bath and cooled to room temperature. To the flask was poured EtOAc (40 mL) and the mixture was transferred into a separatory funnel and washed with aqueous NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to dryness. It was then dissolved in DCM and absorbed into silica gel. The slica gel was then loaded onto a silica column for separation with the solvent systems of hexanes/EtOAc (1/0.3); this gave 2-(methyloxy)-4-prop-2-en-1-ylbenzonitrile. LC-MS (IE, m/z): 174 [M+ 1]+.
- To a 25 mL flask containing a stir bar was added compound 2-(methyloxy)-4-prop-2-en-1-ylbenzonitrile (0.15 g, 0.87 mmol) and MeOH (8 mL). The flask was placed in a cold bath of -78 °C. Ozone was bubbled through the flask for about 10 min. followed by addition of dimethyl sulfide (1.5 mL, 24 mmol). The flask was taken out of the cold bath and stirred at room temperature for 1 h; LC indicated completion of the reaction. The reaction mixture was concentrated to dryness to give 2-(methyloxy)-4-(2-oxoethyl)benzonitrile. LC-MS (IE, m/z): 176 [M + 1]+.
-
- In a 250 mL round bottom flask, (methoxymethyl) (triphenyl)phosphonium chloride (4.0 g, 12 mmol) was dissolved in THF (20 mL). The solution was cooled to -78 °C. To above solution was added n-butyl lithium (3.5 mL, 2.50 M in hexane, 8.7 mmol) dropwise. The color of reaction changed to orange. The mixture was cooled to -78 °C and to it was added 4-oxo-3,4-dihydro-2H-chromeme-7-carbonitrile (1 g, 5.8 mmol). The reaction was let warm to RT and stirred for 18 hours. The reaction was then quenched with addition of saturated ammonium chloride (5 mL) and extracted with dichloromethane. The organic phase was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, concentrated and purified by flash column chromatography (hexane/EtOAc 0-50%). The desired product was obtained (270 mg, 1.34 mmol, 23%). LC-MS (IE, m/z): 202.3 [M + 1]+.
- (4E)-4-(methoxymethylidene)-3,4-dihydro-2H-chromene-7-carbonitrile (230 mg, 1.1 mmol) was dissolved in dichloromethane (6 mL). The solution was cooled to -78 °C. To above solution was added tribromoborane (1.7 mL, 1 M, 1.7 mmol) dropwise over a course of 5 min and subsequently stirred for 30 min at -78 °C. To the reaction mixture was added saturated sodium bicarbonate, extracted with dichloromethane (2 x 20 mL). The organic phase was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, concentrated. The crude product was used without purification. 1H NMR (500 MHz, CDCl3, δ in ppm): 7.0 -7.4 (3H, aromatic), 6.58 (1H, s), 4.55 (2H, m), 2.98 (2H, m).
-
- In a 250 mL round bottom flask, (methoxymethyl) (triphenyl)phosphonium chloride (4.0 g, 12 mmol) was dissolved in THF (20 mL). The solution was cooled to -78 °C. To above solution was added n-butyl lithium (3.50 mL, 2.50 M in Hexane, 8.8 mmol) dropwise. Reaction color changed to orange. The mixture was cooled to -78 °C and to it was added 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (1 g, 5.77 mmol). The reaction was let warm to RT and stirred at r.t for 18 hours. The reaction was then quenched with addition of saturated ammonium chloride (5 mL) and extracted with dichloromethane. The organic phase was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, concentrated and purified by flash column chromatography (Hexane/EtOAc 0-50%). The desired product was obtained. 1H NMR (500 MHz, CDCl3, δ in ppm): 7.0 -7.6 (3H, aromatic), 6.75 (1H, s), 3.88 (3H, s, Me), 3.0 (1H, t), 2.63 (2H, t), 2.23 (1H, t), 2.18 (1H, t), 1.65 (1H, t).
- (5E)-5-(Methoxymethylidene)-5,6,7-8-tetrahydronaphthalene-2-carbonitrile (800 mg, 4.02 mmol) was dissolved in dichloromethane (6 mL). The solution was cooled to -78 °C. To above solution was added tribromoborane (6.0 mL, 1 M, 6.0 mmol) dropwise over a course of 5 min and subsequently stirred for 30 min at -78 °C. To the reaction mixture was added saturated sodium bicarbonate, extracted with dichloromethane (2 x 20 mL). The organic phase was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, concentrated and purified by flash column chromatography. 1H NMR (500 MHz, CDCl3, δ in ppm): 9.6 (1H, s), 7.0 -7.6 (3H, aromatic), 1.8 -3.0 (6H, m).
-
- (3-Fluoro-4-hydroxy-phenyl)-acetic acid (25 g, 150 mmol) was dissolved in methanol (100 mL), and thionyl chloride (5 mL) was added dropwise to the solution. The solution was heated to 85 °C for 16 hours. The reaction mixture was allowed to cool and evaporated to dryness in vacuo. The residue was partitioned between ethyl acetate and saturated NaHCO3. The organic layer was dried over MgSO4, filtered, and the filtrate was evaporated to dryness under reduced pressure to yield the crude title compound as an off white solid (25.3 g). 1H NMR (500 MHz, CDCl3): δ 7.07 (d, J= 7.07 Hz, 1H), 7.00-6.97 (m, 2H), 3.74 (s, 3H), 3.73 (s, 2H).
- The crude phenol [methyl (3-fluoro-4-hydroxyphenyl)acetate, 25.3 g] was dissolved in anhydrous dichloromethane (200 mL). 4-Dimethylaminopyridine (1.68 g) was added, followed by triethylamine (23.0 mL, 165 mmol). The solution was then cooled to in a dry ice and acetone bath while under nitrogen. Trifluoromethanesulfonic anhydride (27.9 mL, 165 mmol) was slowly added and the reaction mixture was allowed to warm to ambient temperature. The reaction mixture was then diluted with dichloromethane (200 mL) and washed with water (2 x 100 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated to dryness under reduced pressure and a cold water bath to yield the crude triflate. LC-MS (IE, m/z): 316 [M+1]+.
- The crude triflate (43.4 g) was subsequently dissolved in anhydrous dimethylformamide (100 mL). Zinc cyanide (7.2 g, 78 mmol) was added, and the solution was purged thoroughly with nitrogen. Tetrakis(triphenylphosphine) palladium (12 g, 14 mmol) was then added and the reaction mixture was heated to 80 °C for 4h. After allowing cooling to ambient temperature and diluting with water (300 mL), ethyl acetate (500 mL) was added. The combined layers were filtered to remove any solids, the filtrate transferred to a separatory funnel, and the layers separated. The aqueous layer was re-extracted with ethyl acetate (1 x 100 mL), the organic portions were combined and dried over magnesium sulfate. The dry organics were then filtered and evaporated to dryness under reduced pressure and excess dimethylformamide was removed by evaporation in vacuo at 65 °C for 1.5 h to yield the crude title compound (42 g). The crude product was purified through silica gel chromatography (ethyl acetate:hexanes = 2:3) to yield the title nitrile. 1H NMR (500 MHz, CDCl3): δ 7.62 (t, J= 6.1 Hz, 1H), 7.23-7.21 (m, 2H), 3.76 (s, 3H), 3.73 (s, 2H). LC-MS (IE, m/z): 194 [M+1]+.
- LiBH4 (1.94 mL, 3.88 mmol, 2 M in THF) was added to a stirred solution of methyl(4-cyano-3-fluorophenyl)acetate (0.50 g, 2.59 mmol) in THF (25 ml) at 0 °C. The resulting solution was stirred for 12 h. Water (10 ml) was added, and the resulting solution was extracted with dichloromethane (2 × 50 ml). The combined organic layers were dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography eluting with EtOAc-Hexanes (7:3 → 1:1) to give the product as colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.60 (dd, J = 7.4, J = 7.1 Hz, 1H), 7.30 (s, 1H), 7.18 (dd, J = 7.3, J = 9.1 Hz, 1H), 3.95 (t, J = 6.2 Hz, 2H), 2.93 (t, J = 6.3 Hz, 2H).
- To a stirred solution of 2-fluoro-4-(2-hydroxyethyl)benzonitrile (0.40 g, 2.4 mmol) in dry CH2Cl2 (20 mL) at 0 °C was added Dess-Martin periodinane (1.54 g, 3.6 mmol) in one portion. The mixture was stirred for 12 h at rt and quenched with a 1:1 mixture of saturated Na2S2O3 (10 mL) and saturated NaHCO3 (10 mL). The resulting mixture was diluted with CH2Cl2 (70 mL) and the layers were separated. The aqueous phase was extracted with CH2Cl2 (2 × 50 mL). The combined organic phases were washed with brine, dried (Na2SO4), and concentrated in vacuo to give crude aldehyde as colorless oil. The residue was used in the next step without further purification. LC-MS (IE, m/z): 164.1 [M+1]+.
-
- To a suspension of NaH (2.6 g, 64 mmol, and 60.0% dispersion in oil) in DMF (80 mL) was added a solution of di-tert-butyl malonate (3.57 g, 16.50 mmol) in DMF (20 mL) at 0 °C and this was stirred for 15 min. Subsequently, 2,4,5-trifluorobenzonitrile (3.0 g, 15.0 mmol) was added in one portion and the reaction mixture was stirred for 8 h at 80 °C and three hours at room temperature. Water (50 mL) was added and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over MgSO4 and filtered. After evaporation in vacuo, the residue was purified by flash chromatography (20% EtOAc in hexane) to give 10.0 g of di-tert-butyl (4-cyano-2,5-difluorophenyl)propanedioate as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.51 (dd, J = 5.5, J = 5.4 Hz, 1H), 7.37 (dd, J = 5, J = 6 Hz, 1H), 4.84 (s, 1H), 1.50 (s, 18H). LC-MS (IE, m/z): 298.2 [(M+1)]+ - t-Bu].
- To the di-tert-butyl (4-cyano-2,5-difluorophenyl)propanedioate (10.0 g, 28.3 mmol) in dichloromethane (30 mL) was added triflouroacetic acid (10 mL) and the mixture stirred for 12 h at room temperature. The solution was concentrated under reduced pressure and chased with toluene (2 x) to give the crude product as a yellowish oil (5g, 90%, 85% purity as indicated by NMR). The residue was used in the next step without further purification. 1H NMR (500 MHz, CDCl3) δ 7.31 (dd, J = 3, J = 2 Hz, 1H), 7.21 (dd, J = 5.8, J = 5.8 Hz, 1H), 3.67 (s, 2H). LC-MS (IE, m/z): 198 [M+1]+.
- (4-Cyano-2,5-difluorophenyl)acetic acid (0.5 g, 2.5 mmol) was dissolved in methanol (20 mL), and thionyl chloride (0.5 mL) was added drop wise to the solution. The reaction was heated to 85° C for 4 hours. Then it was cooled and evaporated to dryness in vacuo. The residue was partitioned between ethyl acetate and saturated NaHCO3. The organic layer was dried over MgSO4, filtered, and the filtrate was evaporated to dryness under reduced pressure to yield the title compound after purification on silica gel (eluted with 5-20% ethyl acetate-hexanes) as an off white solid. 1H NMR (500 MHz, CDCl3): δ 7.31 (dd, J = 5.2, J = 5.2 Hz, 1H), 7.19 (dd, J = 5.7, J = 5.8 Hz, 1H), 3.73 (s, 3H), 3.71 (s, 2H). LC-MS (IE, m/z): 212 [M+1]+.
- LiBH4 (1.45 mL, 2.9 mmol, 2 M in THF) was added to a stirred solution of methyl (4-cyano-2,5-difluorophenyl)acetate (0.47 g, 2.2 mmol) in THF (25 ml) at 0 °C. The resulting solution was stirred for 12 h. Water (15 ml) was added, and the resulting solution was extracted with dichloromethane (2 × 50 ml). The combined organic layers were dried over MgSO4, filtered, and evaporated under reduced pressure to yield the product after purification on silica gel (eluted with 5-30% ethyl acetate-hexanes) as a clear oil. 1H NMR (500 MHz, CDCl3) δ 7.32 (dd, J = 5.3, J = 5.0 Hz, 1H), 7.23 (dd, J = 5.8, J = 5.7 Hz, 1H), 3.95 (t, J = 6.2, J = 6.4 Hz, 2H), 2.98 (t, J = 6.4, J = 6.2 Hz, 2H). LC-MS (IE, m/z): 184 [M+1]+.
- To a stirred solution of 2,5-difluoro-4-(2-hydroxyethyl)benzonitrile (0.36 g, 2.0 mmol) in dry CH2Cl2 (30 mL) at 0 °C was added Dess-Martin periodinane (0.83 g, 2.0 mmol) in one portion. The mixture was stirred for 12 hours at RT and quenched with a 1:1 mixture of saturated Na2S2O3 (10 mL) and saturated NaHCO3 (10 mL). The resulting mixture was diluted with CH2Cl2 (70 mL) and the layers were separated. The aqueous phase was extracted with CH2Cl2 (2 × 50 mL). The combined organic phases were washed with brine, dried (Na2SO4), and concentrated in vacuo to give crude aldehyde as light yellow oil. The residue was used in the next step without further purification and analysis. INTERMEDIATE 24
- To a suspension of NaH (0.37 g, 15.4 mmol, 60.0% dispersion in oil) in DMF (40 mL) was added a solution of di-t-butyl malonate (3.6 g, 16 mmol) in DMF (10 mL) at 0 °C and this was stirred for 15 minutes. Subsequently, 2-bromo-4-fluorobenzonitrile (3.0 g, 15.0 mmol) was added in one portion and the reaction mixture was stirred for 8 hours at 80 °C and three hours at room temperature. Water (50 mL) was added and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over MgSO4 and filtered. After evaporation in vacuo, the residue was purified by flash chromatography (20% EtOAc in hexane) to give di-tert-Butyl (3-bromo-4-cyanophenyl)malonate as a light brown solid. 1H NMR (500 MHz, DMSO-d6) δ 7.97 (d, J = 8 Hz, 1H), 7.88 (s, 1H), 7.60 (d, J = 8 Hz, 1H), 4.95 (s, 1H), 1.42 (s, 18H). LC-MS (IE, m/z): 398 [M+1]+.
- To the di-tert-butyl (3-bromo-4-cyanophenyl)malonate (2.2 g, 5.4 mmol) in dichloromethane (30 mL) was added triflouroacetic acid (10 mL) and the reaction mixture stirred for 12 h at room temperature. The solution was concentrated under reduced pressure and chased with toluene (2x) to give the crude product as a yellowish oil (1g, 77%, and 85% purity as indicated by NMR). The residue was used in the next step without further purification. 1H NMR (500 MHz, DMSO-d6) δ 12.80 (br s, 1H), 7.87 (d, J = 8 Hz,1H), 7.80 (s, 1H), 7.48 (d, J = 8 Hz,1H), 3.73 (s, 2H). LC-MS (IE, m/z): 240 [M+1]+.
- (3-Bromo-4-cyanophenyl)acetic acid (1.0 g, 4.2 mmol) was dissolved in methanol (20 mL), and thionyl chloride (0.5 mL) was added drop wise to the solution. The reaction was heated to 85 °C for 4 h. Then it was cooled to room temperature and evaporated to dryness in vacuo. The residue was partitioned between ethyl acetate and sat. NaHCO3. The organic layer was dried over MgSO4, filtered, and the filtrate was evaporated to dryness under reduced pressure to yield the crude title compound as an off white solid. 1H NMR (500 MHz, CDCl3): δ 7.07 (d, J = 7.07 Hz, 1H), 7.00-6.97 (m, 2H), 3.74 (s, 3H), 3.73 (s, 2H). LC-MS (IE, m/z): 195.2 [(M+1)-CO2CH3]+.
- LiBH4 (1.48 mL, 2.95 mmol, 2 M in THF) was added to a stirred solution of methyl (3-bromo-4-cyanophenyl)acetate (0.50 g, 2.0 mmol) in THF (25 ml) at 0 °C. The resulting solution was stirred for 12 h. Water (15 ml) was added, and the resulting solution was extracted with dichloromethane (2 × 50 ml). The combined organic layers were dried over MgSO4, filtered, and evaporated under reduced pressure to yield the crude product as a cloudy oil. 1H NMR (500 MHz, CDCl3) δ 7.63 (s, 1H), 7.61 (d, J = 5.7,1H), 7.33 (d, J = 7.8 Hz, 1H), 3.93 (t, J = 1.6, J = 4.8 Hz, 2H), 2.92 (t, J= 6.6, J = 5.1 Hz, 2H). LC-MS (IE, m/z): 210.1 [(M+1)]+ - OH].
- To a stirred solution of 2-bromo-4-(2-hydroxyethyl)benzonitrile (0.51 g, 2.3 mmol) in dry CH2Cl2 (30 mL) at 0 °C was added Dess-Martin periodinane (1.45 g, 3.4 mmol) in one portion. The mixture was stirred for 12 h at RT and quenched with a 1:1 mixture of saturated Na2S2O3 (40 mL) and saturated NaHCO3 (40 mL). The resulting mixture was diluted with CH2Cl2 (70 mL) and the layers were separated. The aqueous phase was extracted with CH2Cl2 (2 × 50 mL). The combined organic phases were washed with brine, dried (Na2SO4), and concentrated in vacuo to give crude aldehyde as colorless oil. The residue was used in the next step without further purification and analysis.
-
- The crude phenol [ethyl (4-hydroxy-3-methoxyphenyl) acetate, 12.0 g, 57 mmol] was dissolved in anhydrous dichloromethane (200 mL). 4-Dimethylaminopyridine (0.70 g, 0.10 equiv) was added, followed by triethylamine (9.6 mL, 68 mmol). The solution was then cooled to in a dry ice and acetone bath while under nitrogen. Trifluoromethanesulfonic anhydride (9.6 mL, 57 mmol) was slowly added and the reaction mixture was allowed to warm to ambient temperature. The reaction mixture was then diluted with dichloromethane (200 mL) and washed with water (2 x 100 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to yield the crude triflate. LC-MS (IE, m/z): 269.0 [(M+1)-CO2Et]+.
- The crude triflate (16.6 g) was subsequently dissolved in anhydrous dimethylformamide (100 mL). Zinc cyanide (3.4 g, 29 mmol) was added, and the solution was purged thoroughly with nitrogen. Tetrakis(triphenylphosphine) palladium (5.6 g, 4.8 mmol) was then added and the reaction mixture was heated to 80 °C for 4h. After allowing to cool to ambient temperature and diluting with water (200 mL), ethyl acetate (400 mL) was added. The combined layers were filtered to remove any solids, the filtrate transferred to a separatory funnel, and the layers separated. The aqueous layer was re-extracted with ethyl acetate (2 x 100 mL), the organic portions were combined and dried over magnesium sulfate. The dry organics were then filtered and evaporated to dryness under reduced pressure and excess dimethylformamide was removed by evaporation in vacuo at 65 °C for 1.5 h to yield the crude title compound (20 g). The crude product was purified through silica gel chromatography (ethyl acetate/hexanes, 2:3) to yield the title nitrile. 1H NMR (500 MHz, DMSO-d6 ), δ 7.67 (d, J = 8.0 Hz, 1H), 7.18 (s, 1H), 7.0 (d, J = 8.0 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 3.89 (s, 3H), 3.78 (s, 2H), 1.19 (t, J = 7.1 Hz, 3H); LC-MS (IE, m/z): 220 [M + 1]+.
- To a suspension solution of NaH (0.18 g, 4.6 mmol, 60% dispersion in mineral oil) in THF (50 mL) at °C under N2 atm was added a solution of ethyl (4-cyano-3-methoxyphenyl) acetate (1.0 g, 4.6 mmol) in THF (10 mL) dropwise and the mixture was stirred for 30 min at the same temperature. The mixture was then allowed to warm to ambient temperature. The mixture was then allowed to cool back to 0 °C. Methyl iodide (0.284 mL, 4.56 mmol) was added and the reaction mixture was stirred for 1 h. The reaction mixture was acidified by 1 M hydrochloric acid and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc 15/1) to give ethyl 2-(4-cyano-3-methoxyphenyl) propanoate as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.53 (d, 1H, J = 8 Hz ), 6.98 (d, 1H, J = 8 Hz), 6.95 (s, 1H), 4.17 (q, 2H, J = 3.4 Hz), 3.97 (s, 3H), 3.76 (q, 1H, J = 9.1 Hz), 1.53 (d, 3H, J = 7.1 Hz), 1.25 (t, 3H, J = 7.1 Hz); LC-MS (IE, m/z): 234 [M + 1]+.
- LiBH4 (0.55 mL, 1.09 mmol, 2 M in THF) was added to a stirred solution of ethyl 2-(4-cyano-3-methoxyphenyl) propanoate (0.17 g, 0.73 mmol) in THF (25 ml) at 0 °C. The resulting solution was stirred for 12 h. Water (15 ml) was added, and the resulting solution was extracted with dichloromethane (2 × 50 ml). The combined organic layers were dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography eluting with EtOAc-Hexanes (7:3 → 1:1) to give an inseparable mixture of 4-(1-hydroxypropan-2-yl)-2 methoxybenzonitrile as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.49 (d, 1H, J = 7.9 Hz), 6.88 (dd, 1H, J = 1.4 Hz), 6.83 (s, 1H), 3.92 (s, 3H), 3.72 (d, 2H, J = 6.8 Hz), 2.97 (q, 1H, J = 6.8 Hz), 1.28 (d, 3H, J = 6.9 Hz); LC-MS (IE, m/z): 192.3 [M + 1]+.
- To a stirred solution of 4-(1-hydroxypropan-2-yl)-2-methoxybenzonitrile (0.12 g, 0.63 mmol) in dry CH2Cl2 (30 mL) at 0 °C was added Dess-Martin periodinane (0.35 g, 0.82 mmol) in one portion. The mixture was stirred for 12 h at room temperature and quenched with a 1:1 mixture of saturated Na2S2O3 (20 mL) and saturated NaHCO3 (20 mL). The resulting mixture was diluted with CH2Cl2 (50 mL) and the layers were separated. The aqueous phase was extracted with CH2Cl2 (2 × 50 mL). The combined organic phases were washed with brine, dried (Na2SO4), and concentrated in vacuo to give crude aldehyde as colorless oil. The crude residue was used in the next step without further purification. LC-MS (IE, m/z): 190.3 [M + 1]+.
-
- mL) at °C under N2 was added a solution of ethyl (4-cyano-3-methoxyphenyl) acetate (1.0 g, 4.6 mmol) in THF (10 mL) dropwise and the mixture was stirred for 30 min at the same temperature. The mixture was then allowed to warm to ambient temperature. The mixture was then allowed to cool back to °C. Methyl iodide (0.57 mL, 9.1 mmol) was added and the reaction mixture was stirred for 1 h. The reaction mixture was acidified by 1 M hydrochloric acid and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc 15/1) to give ethyl 2-(4-cyano-3-methoxyphenyl)-2-methylpropanoate as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.54 (d, 1H, J = 8.0 Hz), 7.02 (dd, 1H, J = 1.6 Hz), 6.95 (d, 1H, J = 1.4 Hz), 4.17 (q, 2H, J = 7.2 Hz), 3.96 (s, 3H), 1.61 (s, 6H), 1.23 (t, 3H, J = 7.1 Hz); LC-MS (IE, m/z): 248.3 [M + 1]+.
- LiBH4 (0.48 mL, 0.97 mmol, 2 M in THF) was added to a stirred solution of ethyl 2-(4-cyano-3-methoxyphenyl)-2-methylpropanoate (0.16 g, 0.65 mmol) in THF (25 ml) at 0 °C. The resulting solution was stirred for 12 h. Water (15 ml) was added, and the resulting solution was extracted with dichloromethane (2 × 50 ml). The combined organic layers were dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography eluting with EtOAc-Hexanes (7:3 → 1:1) to give an inseparable mixture of 4-(1-hydroxy-2-methylpropan-2-yl)-2-methoxybenzonitrile as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.55 (d, 1H, J = 8.0 Hz), 6.88 (d, 1H, J = 8.0 Hz), 7.02 (s, 1H), 3.98 (s, 3H), 3.69 (s, 2H), 1.38 (s, 6H); LC-MS (IE, m/z): 206.3 [M+ 1]+.
- To a stirred solution of 4-(1-hydroxy-2-methylpropan-2-yl)-2-methoxybenzonitrile (0.12 g, 0.58 mmol) in dry CH2Cl2 (30 mL) at 0 °C was added Dess-Martin periodinane (0.32 g, 0.76 mmol) in one portion. The mixture was stirred for 12 h at RT and quenched with a 1:1 mixture of saturated Na2S2O3 (20 mL) and saturated NaHCO3 (20 mL). The resulting mixture was diluted with CH2Cl2 (50 mL) and the layers were separated. The aqueous phase was extracted with CH2Cl2 (2 × 50 mL). The combined organic phases were washed with brine, dried (Na2SO4), and concentrated in vacuo to give crude aldehyde as colorless oil. The crude residue was used in the next step without further purification. LC-MS (IE, m/z): 204.4 [M + 1]+.
-
- LiBH4 (0.48 mL, 0.96 mmol, 2 M in THF) was added to a stirred solution of ethyl [6-(1H-tetrazol-1-yl)pyridin-3-yl]acetate (0.150 g, 0.64 mmol) in THF (20 ml) at 0 °C. The resulting solution was stirred for 12 h. Water (5 ml) was added, and the resulting solution was extracted with dichloromethane (2 × 50 ml). The combined organic layers were dried over MgSO4, filtered, and evaporated under reduced pressure to yield the product after flash chromatography (eluted with 10-50% ethyl acetate in hexanes) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 9.51 (s, 1H), 8.43 (br s, 1H), 8.01 (dd, J = 2.7, J = 2.7 Hz, 1H), 7.91 (dd, J = 2.1, J= 2.0 Hz, 1H), 3.99 (br s, 2H), 3.00 (t, J = 6.1, J = 6.2 Hz, 2H). LC-MS (IE, m/z): 164.1 [(M+1)+ - 28].
- To a stirred solution of 2-[6-(1H-tetrazol-1-yl)pyridin-3-yl]ethanol (0.035 g, 0.18 mmol) in dry CH2Cl2 (20 mL) at 0 °C was added Dess-Martin periodinane (0.12 g, 0.28 mmol) in one portion. The mixture was stirred for 12 h at rt and quenched with a 1:1 mixture of saturated Na2S2O3 (5 mL) and saturated NaHCO3 (5 mL). The resulting mixture was diluted with CH2Cl2 (50 mL) and the layers were separated. The aqueous phase was extracted with CH2Cl2 (2 × 50 mL). The combined organic phases were washed with brine, dried (Na2SO4), and concentrated in vacuo to give crude aldehyde as a light yellow solid. The residue was used in the next step without further purification. LC-MS (IE, m/z): 162.1 [(M+1)+- 28].
-
- To a stirred solution of 1.48 g (8.47 mmol) of 2-methoxy-4-(2-oxoethyl)benzonitrile in dichloromethane (30 mL) at 0 °C was added 2.82 mL (8.47 mmol) of a 3.0 M solution of methylmagnesium bromide in THF. The reaction mixture was allowed to warm up to RT and stirred for 12 h. The reaction was then quenched by the addition of 10 mL of 1 N hydrochloric acid and extracted with dichloromethane (2 × 30 mL). The combined organic extracts were dried with magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified on silica (30% EtOAc/hexanes as eluent) to afford 4-(2-hydroxypropyl)-2-methoxybenzonitrile as a clear liquid. 1H NMR (500 MHz, CDCl3) δ 7.47 (d, 1H, J = 7.8 Hz), 6.85 (dd, 1H, J = 3.4 Hz), 6.82 (s, 1H), 4.05 (m, 1H), 3.93 (d, 2H), 3.91 (s, 3H), 1.25 (d, 2H, J = 6.1 Hz). LC-MS (IE, m/z): 192.3 [M+1)+.
- To a stirred solution of 4-(2-hydroxypropyl)-2-methoxybenzonitrile (1.45 g, 7.6 mmol) in dry CH2Cl2 (30 mL) at 0 °C was added Dess-Martin periodinane (4.2 g, 9.8 mmol) in one portion. The mixture was stirred for 12 h at RT and quenched with a 1:1 mixture of saturated Na2S2O3 (20 mL) and saturated NaHCO3 (20 mL). The resulting mixture was diluted with CH2Cl2 (50 mL) and the layers were separated. The aqueous phase was extracted with CH2Cl2 (2 × 50 mL). The combined organic phases were washed with brine, dried (Na2SO4), and concentrated in vacuo to give 2-methoxy-4-(2-oxopropyl)benzonitrile as an oil. The crude residue was used in the next step without further purification. 1H NMR (500 MHz, CDCl3) δ 7.55 (dd, 1H, J = 1.6 Hz), 6.87 (d, 1H, J = 7.8 Hz), 6.83 (s, 1H), 3.96 (s, 3H), 3.79 (s, 2H), 2.25 (s, 3H).
-
- In a 15 mL vial was added 4-fluorobenzene-1,3-diol (500 mg, 3.9 mmol) and 3-chloropropanoic acid (424 mg, 3.9 mmol) and trifluoromethanesulfonic acid (2 mL). The mixture was heated to 80 °C and stirred at that temperature for 4 hour. The reaction was cooled and poured into water (10 mL). The product was extracted with ethyl acetate, dried over anhydrous Na2SO4, filtered, concentrated. To the dark red solid obtained was added sodium hydroxide (2 N, 5 mL) and the solution was let stirred at RT for 18 hours. The mixture was neutralized with 2 N HCl, extracted with EtOAc. The organic phase was dried over anhydrous Na2SO4, filtered, concentrated. The crude was used to next step without purification. 1H NMR (500 MHz, CDCl3, δ in ppm): 7.61 (1H, d, J = 10.3 Hz), 6.56(1H, d, J= 3.1 Hz), 4.48 (2H, t), 2.78 (2H, t).
- In a 100 mL round bottle flask was added 6-Fluoro-7-hydroxy-2,3-dihydro-4H-chromen-4-one (220 mg, 1.2 mmol) and pyridine (10 mL). The solution was cooled to 0 °C. Trifluoromethylsulfonyl anhydride (0.26 mL, 1.6 mmol) was added to above solution dropwise. The reaction was warmed to RT and stirred at that temperature for 2 hours. The mixture was diluted with EtOAc, washed with saturated CuSO4, brine and water. The organic phase was dried over MgSO4, filtered and concentrated. Above crude was purified on flash column chromatography to give the product. LC-MS (IE, m/z): 315.2 [M + 1]+.
- In a 15 mL microwave tube was added 6-Fluoro-4-oxo-3,4-dihydro-2H-chromen-7-yl trifluoromethanesulfonate (370 mg, 1.2 mmol), zinc cyanide (138 mg, 1.2 mmol) and tetrakis(triphenylphosphine)palladium (136 mg, 0.19 mmol, 0.1 eq). The tube was sealed, degased and filled with N2. The mixture was heated to 130 °C in microwave reactor for 30 minutes. The reaction was cooled down, extracted with EtOAc, washed with brine and water. The organic phase was dried over MgSO4, filtered and concentrated. Above crude was purified on flash column chromatography (0 -100% EtOAc/Hex) to give the product as white crystal. LC-MS (IE, m/z): 192.3 [M+ 1]+.
- In a 250 mL round bottom flask, (methoxymethyl) (triphenyl)phosphonium chloride (1.3 g, 3.8 mmol) was dissolved in THF (20 mL). The solution was cooled to -78 °C. To above solution was added n-butyl lithium (0.49 mL, 2.50 M in Hexane, 1.05 mmol) dropwise. Reaction color changed to orange. The mixture was cooled to -78 °C and to it was added 6-Fluoro-4-oxo-3,4-dihydro-2H-chromene-7-carbonitrile (100 mg, 0.52 mmol). The reaction was let warm to RT and stirred at RT for 18 hours. The reaction was then quenched with addition of saturated ammonium chloride (5 mL) and extracted with dichloromethane. The organic phase was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, concentrated and purified by flash column chromatography (hexane/EtOAc 0-50%). The desired product was obtained. LC-MS (IE, m/z): 220.3 [M + 1]+.
- (4E)-6-fluoro-4-(methyoxymethylidene)-3,4-dihydro-2H-chromene-7-carbonitrile (38 mg, 0.17 mmol) was dissolved in dichloromethane (6 mL). The solution was cooled to -78 °C. To above solution was added tribromoborane (260 µL, 1 M, 0.26 mmol) dropwise. The reaction was stirred for 30 min at -78 °C. To the reaction mixture was added saturated sodium bicarbonate, extracted with dichloromethane (2 x 20 mL). The organic phase was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, concentrated and used without purification.
-
- To a solution of methyl (4-cyano-2-fluoro-5-methoxyphenyl)acetate (212 mg, 0.95 mmol) in tetrahydrofuran (4 mL) at 0 °C was added lithium borohydride (2.0 M solution in tetrahydrofuran, 0.62 mL). The mixture warmed slowly to room temperature and was quenched with saturated sodium bicarbonate and diluted with ethyl acetate. The layers were separated and the aqueous extracted with ethyl acetate (2x). The combined organics were washed with water and brine, then dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (MPLC, 5-60% Ethyl Acetate : Hexanes) to provide 5-fluoro-4-(2-hydroxyethyl)-2-methoxybenzonitrile. 1H-NMR (500 MHz, CD3OD) δ ppm 7.22 (m,1H), 6.92 (m,1H), 3.93(s, 3H), 3.88 (m, 2H), 2.95 (m, 2H), 2.29 (br s, 1H).
- To a solution of 5-fluoro-4-(2-hydroxyethyl)-2-methoxybenzonitrile (175 mg, 0.90 mmol) in dichloromethane (4 mL) was added Dess-Martin periodinane (530 mg, 1.3 mmol) at RT. The mixture stirred at roomtemperature for 2 h, then was diluted with saturated sodium bicarbonate and saturated sodium thiosulfate and stirred 30 min. The mixture was extracted with dichloromethane (3x) and the combined organics dried (MgSO4), filtered and concentrated to provide 5-fluoro-2-methoxy-4-(2-oxoethyl)benzonitrile which was used without further purification. LC-MS (IE, m / z ): 194.2 [M + 1]+.
-
- A mixture of 6-amino-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (1.0 g, 5.8 mmol, prepared following the procedure published in J Org. Chem. 1995, 60, 4324-4330) and Boc anhydride in DCM was stirred at RT for 16 hours. The mixture was concentrated and purified by MPLC to furnish 1.14 g of tert-butyl (6-cyano-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate (72% yield). LC-MS (IE, m/z): 273 [M+ 1]+.
- The enantiomers were separated using the AD column with 5% EtOH/heptane. The first peak was assumed as the tert-butyl [(2S)-6-cyano-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate, and the second peak was assumed as the tert-butyl [(2R)-6-cyano-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate.
- The first peak was treated with TFA for 20 minutes to remove the Boc group. When LC suggested the reaction was done, TFA was removed to afford (6S)-6-amino-5,6,7,8-tetrahydronaphthalene-2-carbonitrile. LC-MS (IE, m/z): 173 [M + 1]+.
- To a solution of tert-butyl diallylcarbamate (0.63 g, 3.2 mmol) in DCM at -78 °C was bubbled ozone until a blue color persisted. Nitrogen was bubbled through the reaction to remove excess ozone, followed by addition of a DCM solution of (6S)-6-amino-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (0.14 g, 0.80 mmol) and triethylamine (0.22 mL, 1.6 mmol). Then NaB(OAC)3H (0.85 g, 4.0 mmol) was added to the reaction. The mixture was allowed to warm to RT and stir overnight. LC showed formation of the desired product, which was separated by prep-TLC to furnish 87 mg of tert-butyl 4-[(2S)-6-cyano-1,2,3,4-tetrahydronaphthalen-2-yl]piperazine-1-carboxylate. LC-MS (IE, m/z): 173 [M + 1]+. The material was further treated with TFA to afford crude (6S)-6-piperazin-1-yl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile.
-
- (6R)-6-piperazin-1-yl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile was prepared following the same procedure as INTERMEDIATE 31a from tert-butyl (6-cyano-1,2,3,4-tetrahydronaphthalen-2-yl)carbamate tert-butyl [(2R)-6-cyano-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate.
-
- The preparation of the title compound in Step A was based on a literature procedure as found in Organic Letters, 2007, 9 (9), 1711-1714.
- A suspension of methyl (4-chloro-3-trifluoromethoxyphenyl)acetate (4.8 g, 17.8 mmol) in N,N-dimethylacetamide (50 mL) in a 250 mL round bottomed flask was degassed by bubbling nitrogen for 15 minutes. To this suspension was then added zinc dust (0.23 g, 3.55 mmol), DPPF (0.79 g, 1.42 mmol), Pd2(dba)3 (0.65 g, 0.71 mmol), and Zn(CN)2 (2.50 g, 21.3 mmol) at room temperature. The nitrogen purge was continued for another 15 minutes before the mixture was heated in a 120 °C oil bath for 12 hours. LC-MS indicated that the starting material was consumed to give the product. LC-MS (IE, m/z): 260 [M + 1]+. The mixture was partitioned twice between water and ethyl acetate. The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified on a silica gel column (5-20% ethyl acetate/hexanes) to yield the title product as a yellowish solid. 1H-NMR (500 MHz, CDCl3) δ ppm 3.77 (s, 2H), 3.78 (s, 3H), 7.39 (d, J = 7.5 Hz, 1H), 7.40 (s, 1H), 7.72 (d, J= 7.5 Hz, 1H).
- To a solution of methyl (4-cyano-3-trifluoromethoxyphenyl)acetate (2.15 g, 8.3 mmol) in 1:1 THF:MeOH (10 mL each) was added LiOH-H2O (0.42 g, 10.0 mmol) in water (30 mL). The reaction mixture was stirred at room temperature for 12 hours at which time the starting ester was consumed by TLC (25% ethyl acetate/hexanes). The mixture was concentrated in vacuo and acidified to pH < 3 by dropwise addition of 12N HCl. The acidified solution was then extracted with ethyl acetate, dried over sodium sulfate and concentrated in vacuo to yield the crude title product. LC-MS (IE, m / z): 246 [M + 1]+. 1H-NMR (500 MHz, CDCl3) δ ppm 3.81 (s, 2H), 7.39 (d, J = 7.5 Hz, 1H), 7.40 (s, 1H), 7.75 (d, J = 7.5 Hz, 1H).
- A suspension of (4-cyano-3-trifluoromethoxyphenyl)acetic acid (200 mg, 0.82 mmol) in THF (8 mL) was treated with borane dimethyl sulfide complex (2M, 0.41 mL, 0.82 mmol) and the reaction was stirred overnight at room temperature. The reaction was not complete after 20 hours, so an additional aliquot of borane dimethyl sulfide complex (2M, 0.41 mL, 0.82 mmol) was added. After stirring for another 1 hour at room temperature, the reaction was quenched with methanol and the mixture was partitioned with ethyl acetate and 2N HCl/water. The aqueous was extracted again with ethyl acetate and the organic layers were washed with brine, dried over sodium sulfate and evaporated. The residue was purified on a CombiFlash Rf (12 gm, gradient 10-80% ethyl acetate in hexanes) to afford the title alcohol (142 mg) as an oil. 1H-NMR (500 MHz, CDCl3) δ ppm 1.62 (s, 1H), 2.971 (t, J = 6.4 Hz, 2H), 3.936 (t, J= 6.4 Hz, 2H), 7.315 (s, 1H), 7.322 (d, J = 8.5 Hz, 1H), 7.660 (d, J = 8.5 Hz, 1H).
- A solution of 4-(2-hydroxethyl)-2-(trifluoromethoxy)benzonitrile (140 mg, 0.61 mmol) in DCM (3 mL) was treated with Dess-Martin periodinane (360 mg, 0.85 mmol) and was stirred at room temperature for 1.5 hours. MS/LC showed mostly aldehyde product by UV (no M+1 detected in the MS) and a small amount of alcohol. After a total of 2.25 hours the reaction was quenched by partitioning with DCM and water containing sodium bicarbonate and sodium thiosulfate (3x). The organic layer was then washed with brine, dried over sodium sulfate and evaporated to give crude title aldehyde as an oil which was used directly in subsequent reductive amination reactions.
-
- A suspension of (3-chloro-4-cyanophenyl)acetic acid (200 mg, 1.02 mmol) in THF (8 mL) was treated with borane dimethyl sulfide complex (2M, 0.5 mL, 1.0 mmol) and the reaction was stirred overnight at room temperature. The reaction was not complete after 20 hours, so an additional aliquot of borane dimethyl sulfide complex (2M, 0.5 mL, 1.0 mmol) was added. After stirring for another 1 hour at room temperature, the reaction was quenched with methanol and the mixture was partitioned with ethyl acetate and 2N HCl/water. The aqueous layer was extracted again with ethyl acetate and the organic layers were washed with brine, dried over sodium sulfate and evaporated. The residue (199 mg) was purified on a CombiFlash Rf (12 gm, gradient 10-80% ethyl acetate in hexanes) to afford the title alcohol as an oil. 1H-NMR (500 MHz, CDCl3) δ ppm 1.62 (s, 1H), 2.925 (t, J = 6.4 Hz, 2H), 3.92 (t, J = 6.4 Hz, 2H), 7.27 (d, J = 7.5 Hz, 1H), 7.44 (s, 1H), 7.62 (d, J = 8.1 Hz, 1H).
- A solution of 2-chloro-4-(2-hydroxethyl)benzonitrile (160 mg, 0.88 mmol) in DCM (3 mL) was treated with Dess-Martin periodinane (520 mg, 1.2 mmol) and was stirred at room temperature for 1.5 hours. LC-MS showed an aldehyde peak by UV (no M+1 detected in the MS) and a small amount of alcohol starting material. After a total of 2.25 hours the reaction was quenched by partitioning with DCM and water containing sodium bicarbonate and sodium thiosulfate (3x). The organic layer was then washed with brine, dried over sodium sulfate and evaporated to give crude title aldehyde as an oil which was used directly in subsequent reductive amination reactions.
-
- A suspension of (4-cyano-2-fluoro-3-methoxyphenyl)acetic acid (200 mg, 0.96 mmol) in THF (8 mL) was treated with borane dimethyl sulfide complex (2M, 0.96 mL, 1.9 mmol) and the reaction was stirred for 3 hours at room temperature. The reaction was quenched with methanol and the mixture was partitioned with ethyl acetate and 2N HCl/water. The aqueous was extracted again with ethyl acetate and the organic layers were washed with brine, dried over sodium sulfate and evaporated The residue was purified on a CombiFlash Rf (12 gm, gradient 10-80% ethyl acetate in hexanes) to afford the title alcohol as an oil. LC-MS (IE, m/z): 196 [M + 1]. 1H-NMR (500 MHz, CDCl3) δ ppm 1.60 (br s, 1H), 2.891 (t, J = 6.4 Hz, 2H), 3.834 (t, J = 6.4 Hz, 2H), 4.055 (s, 3H), 6.952 (t, J = 8.1 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H).
- A solution of 3-fluoro-2-methoxy-4-(2-hydroxethyl)benzonitrile (60 mg, 0.31 mmol) in DCM (5 mL) was treated with Dess-Martin periodinane (183 mg, 0.43 mmol) and was stirred at room temperature for 2.5 hours. LC-MS showed the aldehyde product peak by UV (no M+1 detected in the MS) and a small amount of starting material alcohol. The reaction was quenched by partitioning with DCM and water containing sodium bicarbonate and sodium thiosulfate (3x). The organic layer was then washed with brine, dried over sodium sulfate and evaporated to give crude title aldehyde as an oil which was used directly in subsequent reductive amination reactions.
-
- A suspension of (4-cyanonaphthalen-1-yl)acetic acid (100 mg, 0.47 mmol) in THF (6 mL) was treated with borane dimethyl sulfide complex (2M, 0.47 mL, 0.94 mmol) and the reaction was stirred for 3 hours at room temperature. The reaction was quenched with methanol and the mixture was partitioned with ethyl acetate and 2N HCl/water. The aqueous was extracted again with ethyl acetate and the organic layers were washed with brine, dried over sodium sulfate and evaporated. The residue was purified on a CombiFlash Rf (12 gm, gradient 10-80% ethyl acetate in hexanes) to afford the title alcohol as an oil. 1H-NMR (500 MHz, CDCl3) δ ppm 1.80 (br s, 1H), 3.48 (t, J = 6.4 Hz, 2H), 4.10 (t, J = 6.4 Hz, 2H), 7.52 (d, J = 7.3 Hz, 1H), 7.75 (m, 2H), 7.92 (d, J = 7.2 Hz, 1H), 8.22 (d, J = 8.2 Hz, 1H), 8.34 (d, J = 8.0 Hz, 1H).
- A solution of 4-(2-hydroxyethyl)naphthalene-1-carbonitrile (25 mg, 0.13 mmol) in DCM (4 mL) was treated with Dess-Martin periodinane (75 mg, 0.18 mmol) and was stirred at room temperature for 3 hours. The reaction was quenched by partitioning with DCM and water containing sodium bicarbonate and sodium thiosulfate (3x). The organic layer was then washed with brine, dried over sodium sulfate and evaporated to give the title aldehyde as an oil which was used directly in subsequent reductive amination reaction.
-
- A suspension of (4-cyano-3-ethoxyphenyl)acetic acid (100 mg, 0.49 mmol) in THF (5 mL) was treated with borane dimethyl sulfide complex (2M, 0.49 mL, 0.98 mmol) and the reaction was stirred 1 hour at room temperature. The reaction was not complete, so an additional aliquot of borane dimethyl sulfide complex (2M, 0.49 mL, 0.98 mmol) was added. After stirring for another 1 hour at room temperature, the reaction was quenched with methanol and the mixture was partitioned with ethyl acetate and 2N HCl/water. The aqueous was extracted again with ethyl acetate and the organic layers were washed with brine, dried over sodium sulfate and evaporated. The residue was purified on a silica gel column (gradient 20-50% ethyl acetate in hexanes) to afford the title alcohol as an oil. 1H-NMR (500 MHz, CDCl3) δ ppm 1.451 (t, J = 7.0 Hz, 3H), 1.76 (br s, 1H), 2.865 (t, J = 6.3 Hz, 2H), 3.863 (t, J = 6.3 Hz, 2H), 4.127 (q, J = 7.0 Hz, 2H), 6.814 (s, 1H), 6.841 (d, J = 7.9 Hz, 1H), 7.449 (d, J = 7.7 Hz, 1H).
- A solution of 2-(ethoxy)-4-(2-hydroxethyl)benzonitrile (56 mg, 0.29 mmol) in DCM (5 mL) was treated with Dess-Martin periodinane (250 mg, 0.59 mmol) and was stirred at room temperature for 2.5 hours. The reaction was quenched by partitioning with DCM and water containing sodium bicarbonate and sodium thiosulfate (3x). The organic layer was then washed with brine, dried over sodium sulfate and evaporated to give the title aldehyde as an oil which was used directly in subsequent reductive amination reactions.
-
- A suspension of (4-cyano-2,3,6-trifluorophenyl)acetic acid (140 mg, 0.65 mmol) in THF (8 mL) was treated with borane dimethyl sulfide complex (2M, 0.65 mL, 1.30 mmol) and the reaction
- was stirred for 3 hours at room temperature. The reaction was quenched with methanol and the mixture was partitioned with ethyl acetate and 2N HCl/water. The aqueous was extracted again with ethyl acetate and the organic layers were washed with brine, dried over sodium sulfate and evaporated. The residue was purified on a silica gel column (gradient 30-50% ethyl acetate in hexanes) to afford the title alcohol as an oil. 1H-NMR (500 MHz, CDCl3) δ ppm 1.50 (br s, 1H), 2.959 (t, J = 6.5 Hz, 2H), 3.820 (t, J = 6.5 Hz, 2H), 7.064 (br t, 1H).
- A solution of 4-(2-hydroxethyl)-2,3,5-trifluorobenzonitrile (44 mg, 0.22 mmol) in DCM (5 mL) was treated with Dess-Martin periodinane (186 mg, 0.44 mmol) and was stirred at room temperature for 1.5 hours when another aliquot of periodinane (50 mg) was added. After 2.5 hours, the reaction was quenched by partitioning with DCM and water containing sodium bicarbonate and sodium sulfite (3x). The organic layer was then washed with brine, dried over sodium thiosulfate and evaporated to give the title aldehyde as an oil which was used directly in subsequent reductive amination reactions.
-
- tert-Butyl methyl malonate (7.5 g, 43 mmol) in anhydrous DMF (50 mL) under nitrogen was cooled in an ice bath. Sodium hydride (60% in mineral oil, 1.00 g, 42 mmol) was added portionwise over 5 minutes. The reaction was allowed to warm to room temperature for 30 minutes at which time all was in solution and hydrogen gas had ceased. To the solution was then added 2,4-difluoro-3-chlorobenonitrile (5.0 g, 29 mmol) as a solid in one portion. The reaction was heated in a 90 °C oil bath for 4 hours and then stirred at room temperature for 16 hours. The reaction was quenched by addition of 2N HCl in water. The mixture was partitioned with ether (2x), and the organic layers were washed with brine, dried over sodium sulfate and evaporated in vacuo. TLC (15% ethyl acetate/hexanes) indicated a small amount of di-fluoro starting material, but mostly the desired product and excess malonate. The crude residue was purified by flash chromatography (5-10% % ethyl acetate/hexanes to elute excess malonate and starting material, then 10-20% ethyl acetate/hexanes for products). The first product fractions were a mixture with some of the minor t-butyl methyl (2-chloro-6-cyano-3-fluorophenyl)malonate side product isomer (900 mg, mostly desired title product by NMR), then later fractions were clean desired title isomer. 1H-NMR (500 MHz, CDCl3) δ ppm 1.464 (s, 9H), 3.793 (s, 3H), 5.145 (s, 1H), 7.448 (d, J = 8.3 Hz, 1H), 7.560 (dd, J = 6.2 and 8.3 Hz, 1H).
- To a solution of t-butyl methyl (2-chloro-4-cyano-3-fluorophenyl)malonate (4.8 g, 15 mmol) in DCM (50 mL) was added TFA (50 mL) at room temperature and the mixture was aged for 20 hours. LC-MS and TLC (20% ethyl acetate/hexanes) indicated lack of starting malonate diester, but still some mono-acid/mono-ester intermediate. The volatiles were removed in vacuo and the residue was taken up in methanol and heated to reflux for 1 hour. The volatiles were again removed in vacuo and the residue was purified on a CombiFlash Rf (40 gm, 10-40% ethyl acetate /hexanes) to give several main fractions of clean title product by NMR. 1H-NMR (500 MHz, CDCl3) δ ppm 3.734 (s, 3H), 3.860 (s, 2H), 7.234 (d, J = 8.0 Hz, 1H), 7.512 (dd, J = 6.1 and 8.0 Hz, 1H).
- A suspension of methyl (2-chloro-4-cyano-3-fluorophenyl)acetate (400 mg, 1.8 mmol) in THF (5 mL) was treated with lithium borohydride solution in THF (2M, 1.1 mL, 2.2 mmol) and the reaction was stirred overnight at room temperature. The reaction was quenched with 2N HCl and the mixture was partitioned with ethyl acetate and water. The aqueous was extracted again with ethyl acetate and the organic layers were washed with brine, dried over sodium sulfate and evaporated. The residue was purified on a CombiFlash Rf (24 gm, gradient 10-40% ethyl acetate in hexanes) to afford the title alcohol. 1H-NMR (500 MHz, CDCl3) δ ppm 1.66 (br s, 1H), 3.088 (t, J = 6.4 Hz, 2H), 3.922 (t, J = 6.4 Hz, 2H), 7.242 (d, J = 8.1 Hz, 1H), 7.469 (dd, J = 6.5 and 8.1 Hz, 1H).
- A solution of 3-chloro-2-fluoro-4-(2-hydroxethyl)benzonitrile (62 mg, 0.31 mmol) in DCM (6 mL) was treated with Dess-Martin periodinane (263 mg, 0.621 mmol) and was stirred at room temperature for 2 hours. The reaction was quenched by stirring with water containing sodium bicarbonate and sodium sulfite for 30 minutes. The mixture was extracted twice with DCM and the organic layers were washed with brine, dried over sodium sulfate and evaporated to give the crude title aldehyde which was used directly in subsequent reductive amination reactions. NMR of the crude mixture indicated a mixture of aldehyde and some periodinane by-product. 1H-NMR (500 MHz, CDCl3) δ ppm 4.032 (s, 2H), 7.190 (d, J = 8.0 Hz, 1H), 7.571 (d, J = 8.1 Hz, 1H), 9.820 (s, 1H).
-
- A solution of methyl (2-chloro-4-cyano-3-fluorophenyl)acetate (1.40 g, 6.2 mmol) from example XX, Step B, was divided into 2 reactions in 2x20 mL Micro Wave (MW) vials, potassium carbonate (0.85 g, 6.2 mmol each vial) and MeOH (15 mL each vial) were added. Each reaction was heated at 130 °C for 60 minutes. The reactions were combined and concentrated, the residue was diluted with water, acidified with 2M HCl and extracted 2x with ethyl acetate, and the organic layers were washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was taken up in 1:1 MeOH:DCM (40 mL) and excess 2M trimethylsilyldiazomethane in ether was added until the yellow color persisted, the excess was quenched with acetic acid and the solution was concentrated in vacuo. Flash chromatography (40% DCM/hexanes to 100% DCM) gave the title ester. 1H-NMR (500 MHz, CDCl3) δ ppm 3.724 (s, 3H), 3.829 (s, 2H), 4.069 (s, 3H), 7.139 (d, J = 8.0 Hz, 1H), 7.465 (d, J = 8.0 Hz, 1H).
- A suspension of methyl (2-chloro-4-cyano-3-methoxyphenyl)acetate (700 mg, 2.9 mmol) in THF (15 mL) was treated with lithium borohydride solution in THF (2M, 1.46 mL, 2.9 mmol) and the reaction was stirred overnight at room temperature. The reaction was quenched with 2N HCl and the mixture was partitioned with ethyl acetate and water. The aqueous layer was extracted again with ethyl acetate and the organic layers were washed with brine, dried over sodium sulfate and evaporated. The residue was purified on a silica gel column (gradient 10-40% ethyl acetate in hexanes) to afford the title alcohol as a white solid. LC-MS (IE, m/z): 212 [M + 1]+. 1H-NMR (500 MHz, CDCl3) δ ppm 1.58 (br s, 1H), 3.096 (t, J = 6.5 Hz, 2H), 3.943 (t, J = 6.4 Hz, 2H), 4.083 (s, 3H), 7.175 (d, J = 7.8 Hz, 1H), 7.462 (d, J = 8.0 Hz, 1H).
- A solution of 3-chloro-2-methoxy-4-(2-hydroxethyl)benzonitrile (80 mg, 0.38 mmol) in DCM (6 mL) was treated with Dess-Martin periodinane (320 mg, 0.76 mmol) and was stirred at room temperature for 2.5 hours. LC-MS showed an aldehyde peak by UV (no M+1 detected in the MS) and a small amount of alcohol. The reaction was quenched by partitioning with DCM and water containing sodium bicarbonate and sodium thiosulfate (3x). The organic layer was then washed with brine, dried over sodium sulfate and evaporated to give crude title aldehyde as an oil which was used directly in subsequent reductive amination reactions. NMR of the crude mixture indicated a mixture of aldehyde and periodinane by-product. 1H-NMR (500 MHz, CDCl3) δ ppm 3.976 (s, 2H), 4.101 (s, 3H), 7.112 (d, J = 8.0 Hz, 1H), 7.513 (d, J = 8.0 Hz, 1H), 9.798 (s, 1H).
-
- (prepared from 5-chloro-2,4-difluorobenzonitrile as in Intermediate 39) in THF (7 mL) was treated with lithium borohydride solution in THF (2M, 1.1 mL, 2.2 mmol) and the reaction was stirred overnight at room temperature. The reaction was nearly complete after 20 hours by LC-MS from the UV trace. The reaction was quenched 2N HCl and the mixture was partitioned with ethyl acetate and water. The aqueous layer was extracted again with ethyl acetate and the organic layers were washed with brine, dried over sodium sulfate and evaporated. The residue was purified on a CombiFlash Rf (12 gm, gradient 10-20% ethyl acetate in hexanes with 5% DCM for solubility) to afford the title alcohol as an oil. 1H-NMR (500 MHz, CDCl3) δ ppm 1.45 (br s, 1H), 3.01 (t, J = 6.4 Hz, 2H), 3.92 (t, J = 6.4 Hz, 2H), 7.218 (d, J = 9.3 Hz, 1H), 7.581 (d, J = 5.7 Hz, 1H).
- A solution of 5-chloro-2-fluoro-4-(2-hydroxethyl)benzonitrile (85 mg, 0.88 mmol) in DCM (5 mL) was treated with Dess-Martin periodinane (360 mg, 0.85 mmol) and was stirred at room temperature for 2.5 hours. The reaction was quenched by partitioning with DCM and water containing sodium bicarbonate and sodium thiosulfate (3x). The organic layer was then washed with brine, dried over sodium sulfate and evaporated to give crude title aldehyde as an oil which was used directly in subsequent reductive amination reactions. NMR of the crude product indicated a mixture of aldehyde and still some periodinane by-product. 1H-NMR (500 MHz, CDCl3) δ ppm 3.967 (s, 2H), 7.172 (d, J = 8.7 Hz, 1H), 7.693 (d, J = 5.7 Hz, 1H), 9.802 (s, 1H).
-
- To a solution of methyl (2-chloro-4-cyano-5-fluorophenyl)acetate (0.55 g, 2.4 mmol), which was prepared as in the synthesis of Intermediate 40, in MeOH (15 mL) in a 20 mL MW vial was added potassium carbonate (1.00 g, 7.2 mmol). The reaction was heated at 130 °C for 45 minutes. The reaction was then concentrated, the residue was diluted with water, acidified with 2M HCl and extracted 2x with ethyl acetate, and the organic layers were washed with brine, dried over sodium sulfate and evaporated in vacuo. Flash chromatography (10-50% ethyl acetate/hexanes with 1% HOAc) gave the title acid as a white solid. 1H-NMR (500 MHz, CDCl3) δ ppm 3.77 (s, 2H), 3.90 (s, 3H), 6.90 (s, 1H), 7.53 (s, 1H).
- (2-Chloro-4-cyano-5-methoxyphenyl)acetic-acid (545 mg, 2.4 mmol) was taken up in 1:1 MeOH:DCM (50 mL) and excess 2M trimethylsilyldiazomethane in ether was added until the yellow color persisted, the excess was quenched with acetic acid and the solution was concentrated in vacuo. Flash chromatography (10-50% ethyl acetate/hexanes) gave the title ester as a white solid. 1H-NMR (500 MHz, CDCl3) δ ppm 3.703 (s, 3H), 3.767 (s, 2H), 3.897 (s, 3H), 6.896 (s, 1H), 7.526 (s, 1H).
- A suspension of methyl (2-chloro-4-cyano-5-methoxyphenyl)acetate (200 mg, 2.9 mmol) in THF (15 mL) was treated with lithium borohydride solution in THF (2M, 1.46 mL, 2.9 mmol) and the reaction was stirred overnight at room temperature. The reaction was quenched with 2N HCl and the mixture was partitioned with ethyl acetate and water. The aqueous layer was extracted again with ethyl acetate and the organic layers were washed with brine, dried over sodium sulfate and evaporated. The residue was purified on a silica gel column (gradient 10-40% ethyl acetate in hexanes) to afford the title alcohol as a white solid. 1H-NMR (500 MHz, CDCl3) PPM 1.558 (br s, 1H), 3.035 (t, J = 6.5 Hz, 2H), 3.927 (t, J = 6.4 Hz, 2H), 3.927 (s, 3H), 6.927 (s, 1H), 7.536 (s, 1H).
- A solution of 5-chloro-2-methoxy-4-(2-hydroxethyl)benzonitrile (60 mg, 0.33 mmol) in DCM (6 mL) was treated with Dess-Martin periodinane (281 mg, 0.66 mmol) and was stirred at room temperature for 2.5 hours. The reaction was quenched by partitioning with DCM and water containing sodium bicarbonate and sodium thiosulfate (3x). The organic layer was then washed with brine, dried over sodium sulfate and evaporated to give crude title aldehyde as an oil which was used directly in subsequent reductive amination reactions. NMR of the crude mixture indicated a mixture of aldehyde and periodinane by-product. 1H-NMR (500 MHz, CDCl3) δ ppm 3.951 (s, 2H), 3.958 (s, 3H), 6.880 (s, 1H), 7.625 (s, 1H), 9.810 (s, 1H).
-
- t-Butyl methyl malonate (0.71 g, 4.1 mmol) in anhydrous DMF (20 mL) under nitrogen was cooled in an ice bath. Sodium hydride (60% in mineral oil, 176 mg, 7.4 mmol) was added portionwise over 5 minutes. The reaction was allowed to warm to room temperature for 30 minutes at which time all was in solution and hydrogen gas had ceased. To the solution was then added 2,4-difluoro-3-methylbenonitrile (0.500 g, 3.3 mmol) as a solid in one portion. The reaction was heated in a 95 °C oil bath for 5 hours and then stirred at room temperature for 16 hours. The reaction was quenched by addition of 2N HCl in water. The mixture was portioned with ether (2x), and the organic layers were washed with brine, dried over sodium sulfate and evaporated in vacuo. TLC (10% ethyl acetate/hexanes) indicated a small amount of di-fluoro starting material, major desired product plus some minor isomer (slightly higher Rf) and excess malonate. The crude residue was purified by FC (5-7% to elute excess malonate, starting material and minor isomer, then 10-15% ethyl acetate/hexanes to elute the product) to afford several clean product fractions. 1H-NMR (500 MHz, CDCl3) δ ppm 1.371 (s, 9H), 2.200 (s, 3H), 3.692 (s, 3H), 4.725 (s, 1H), 7.237 (d, J = 8.2 Hz, 1H), 7.389 (br t, J = 7.3 Hz, 1H).
- To a solution of tert-Butyl methyl (4-cyano-3-fluoro-2-methylphenyl)malonate (0.75 g, 2.4 mmol) in DCM (10 mL) was added TFA (10 mL) at room temperature and the mixture was aged for 3 hours. LC-MS and TLC (15% ethyl acetate/hexanes) indicated the lack of starting diester, but still some mono-acid/mono-ester intermediate. The volatiles were removed in vacuo and the residue was taken up in dioxane with a few drops of acetic acid and heated to reflux for 1 hour. The volatiles were again removed in vacuo and the residue was purified by flash chromatography (5-15% ethyl acetate /hexanes) to give several main fractions of clean title ester product. 1H-NMR (500 MHz, CDCl3) δ ppm 2.254 (s, 3H), 3.709 (s, 5H), 7.102 (d, J = 8.0 Hz, 1H), 7.414 (br t, J = 7.3 Hz, 1H).
- A suspension of methyl (4-cyano-3-fluoro-2-methylphenyl)acetate (170 mg, 0.82 mmol) in THF (3 mL) was treated with lithium borohydride solution in THF (2M, 0.82 mL, 1.6 mmol) and the reaction was stirred overnight at room temperature. The reaction was quenched with 2N HCl and the mixture was partitioned with ethyl acetate and water. The aqueous was extracted again with ethyl acetate and the organic layers were washed with brine, dried over sodium sulfate and evaporated. The residue was purified on a silica gel column (gradient 10-40% ethyl acetate in hexanes) to afford the title alcohol as an oil. 1H-NMR (500 MHz, CDCl3) δ ppm 1.88 (br s, 1H), 2.303 (s, 3H), 2.971 (t, J = 6.6 Hz, 2H), 3.886 (t, J = 6.6 Hz, 2H), 7.129 (d, J = 8.0 Hz, 1H), 7.403 (br t, J = 7.5 Hz, 1H).
- A solution of 2-fluoro-3-methyl-4-(2-hydroxethyl)benzonitrile (66 mg, 0.37 mmol) in DCM (5 mL) was treated with Dess-Martin periodinane (312 mg, 0.74 mmol) and was stirred at room temperature for 2.5 hours. The reaction was quenched by partitioning with DCM and water containing sodium bicarbonate and sodium thiosulfate. The organic layer was then washed with brine, dried over sodium sulfate and evaporated to give crude title aldehyde as an oil which was used directly in subsequent reductive amination reactions. NMR of the crude product indicated a mixture of aldehyde and still some periodinane by-product. 1H-NMR (500 MHz, CDCl3) δ ppm 2.210 (s, 3H), 3.846 (s, 2H), 7.054 (d, J = 8.0 Hz, 1H), 7.449 (br t, J = 8.0 Hz, 1H), 9.757 (s, 1H).
-
- A solution of methyl (4-cyano-3-fluoro-2-methylphenyl)acetate (0.38 g, 1.8 mmol) from the Example 42, Step B, was taken up in methanol (6 mL), potassium carbonate (0.51 g, 3.7 mmol) was added and the reaction was heated at 135 °C for 2.5 hours (not complete after 1 hour). The reaction was concentrated, the residue was diluted with water and extracted 2x with ethyl acetate, and the organic layers were washed with brine, dried over sodium sulfate and evaporated in vacuo. Flash chromatography (5-10% ethyl acetate/hexanes) still gave a mixture so repeated chromatography (25-100% DCM in hexanes) gave clean title ester (220 mg). 1H-NMR (500 MHz, CDCl3) δ ppm 2.22 (s, 3H), 3.68 (s, 2H), 3.70 (s, 3H), 3.97 (s, 3H), 7.04 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H).
- A suspension of methyl (4-cyano-3-methoxy-2-methylphenyl)acetate (175 mg, 0.80 mmol) in THF (5 mL) was treated with lithium borohydride solution in THF (2M, 0.79 mL, 1.6 mmol) and the reaction was stirred overnight at room temperature. The reaction was quenched with 2N HCl and the mixture was partitioned with ethyl acetate and water. The aqueous layer was extracted again with ethyl acetate and the organic layers were washed with brine, dried over sodium sulfate and evaporated. The residue was purified on a silica gel column (gradient 10-15% ethyl acetate in hexanes to elute some remaining starting material, then 15-25% to elute the product) to afford the title alcohol. 1H-NMR (500 MHz, CDCl3) δ ppm 1.57 (br s, 1H), 2.266 (s, 3H), 2.931 (t, J = 6.8 Hz, 2H), 3.860 (t, J = 6.8 Hz, 2H), 3.961 (s, 3H), 7.030 (d, J = 8.1 Hz, 1H), 7.374 (d, J = 8.1 Hz, 1H).
- A solution of 2-methoxy-3-methyl-4-(2-hydroxethyl)benzonitrile (60 mg, 0.31 mmol) in DCM (5 mL) was treated with Dess-Martin periodinane (266 mg, 0.63 mmol) and was stirred at room temperature for 2 hours. MS/LC showed an aldehyde peak by UV (no M+1 detected in the MS) and no alcohol. The reaction was quenched by partitioning with DCM and water containing sodium bicarbonate and sodium thiosulfate. The organic layer was then washed with brine, dried over sodium sulfate and evaporated to give crude title aldehyde as an oil which was used directly in subsequent reductive amination reactions. LC-MS of the crude mixture (72 mg) indicated a mixture of aldehyde and a trace of periodinane by-product.
-
- To 4-fluoro-2-methoxybenzonitrile (3.00 g, 20 mmol) and N-iodosuccinimide (NIS) (4.7 g, 21 mmol) under nitrogen was added TFA (35 mL) and the reaction was stirred at room temperature for 20 hours. The volatiles were removed in vacuo and the residue was taken up in 1:1 ethyl acetate:ether and was washed with aqueous sodium bicarbonate and then brine containing enough sodium sulfite to remove the iodine color. The aqueous layers were back extracted with more 1:1 ethyl acetate:ether and the combined organic layers were dried over sodium sulfate and evaporated. The residue was treated with ether/hexanes to afford clean iodo title product as a white solid. 1H-NMR (500 MHz, CDCl3) δ ppm 3.930 (s, 3H), 6.730 (d, J = 9.4 Hz, 1H), 7.900 (d, J = 6.8 Hz, 1H).
- To a mixture of 4-fluoro-5-iodo-2-methoxybenzonitrile (2.5 g, 9.0 mmol), Pd(Ph3P)4 (1.0 g, 0.90 mmol) and lithium chloride (0.96 g, 23 mmol) under nitrogen was added anhydrous toluene (50 mL) and the mixture was flushed (3x) with nitrogen. Allyltributyltin (4.15 mL, 14 mmol) was added and the mixture was flushed again with nitrogen. The reaction was heated under nitrogen at 115 °C for 2.5 hours and then let cool to room temperature. TLC (10% ethyl acetate/Hexanes) showed several spots with a strongly charring product spot right above the starting material. The reaction was diluted with hexanes and filtered to remove insoluble material. The mother liquor was concentrated and the residue was purified on a Biotage 65+M column with a gradient elution from 0 to 40% ethyl acetate in hexanes to afford the title product which had some residual tributylstanane by-product contaminant by NMR. 1H-NMR (500 MHz, CDCl3) δ ppm 3.327 (d, J = 6.5 Hz, 2H), 3.902 (s, 3H), 5.102 (2 d, J = 10.0 and 17 Hz, 2H), 5.868 (m, 1H), 6.668 (d, J = 11.1 Hz, 1H), 7.390 (d, J = 8.0 Hz, 1H).
- A solution of 4-fluoro-2-methoxy-5-(prop-2-en-1-yl)benzonitrile (1.2 g, 6.0 mmol) in methanol (50 mL) was cooled in a dry ice acetone bath and treated with ozone. Since the starting material was contaminated with some tributylstanane residue from the previous reaction, the reaction turned brown at first. The mixture was flushed with nitrogen and quenched with dimethylsulfide (4 mL). The solution was allow to warm to about 0 °C which resulted in a clear yellow solution and then sodium borohydride (0.27 g, 7.2 mmol) was added under nitrogen and the reaction was stirred for 30 minutes at room temperature. TLC of an aliquot in ether/water (30% ethyl acetate in hexanes) indicated a product band without evidence of starting material. After a total of 1 hour, the reaction was quenched with 18% aqueous citric acid and concentrated in vacuo to remove the methanol. The residue was partitioned between ethyl acetate and 18% citric acid, washed with brine, dried over sodium sulfate and evaporated. Purification of the residue with a Biotage 40+M column (10 to 60 % ethyl acetate in hexanes) gave the title alcohol as a white solid. 1H-NMR (500 MHz, CDCl3) δ ppm 1.60 (br s, 1H), 2.842 (t, J = 6.5 Hz, 2H), 3.853 (t, J = 6.5 Hz, 2H), 3.904 (s, 3H), 6.682 (d, J = 11.2 Hz, 1H), 7.487 (d, J = 8.1 Hz, 1H).
- A solution of 4-fluoro-5-(2-hydroxyethyl)-2-methoxybenzonitrile (72 mg, 0.37 mmol) in DCM (5 mL) was treated with Dess-Martin periodinane (313 mg, 0.74 mmol) and was stirred at room temperature for 3 hours. The reaction was quenched by partitioning with DCM and water containing sodium bicarbonate and sodium thiosulfate for 30 minutes. The organic layer was then washed with brine, dried over sodium sulfate and evaporated to give crude title aldehyde as an oil which was used directly in subsequent reductive amination reactions. NMR of the crude mixture indicated an apparent mixture of aldehyde and acid (2:1 ratio) and some periodinane by-product. 1H-NMR (500 MHz, CDCl3) δ ppm 3.726 and 3.741 (2 s, 2H, 2:1 ratio), 3.933 (s, 3H), 6.745 (d, J = 11.0 Hz, 1H), 7.419 and 7.490 (2 d, J = 8.0 Hz, 1H, 2:1 ratio).
- Final products in the Examples are named as their free base/free acid forms, although synthesis of some of the compounds may have resulted in a salt form of the final product. IC50 results derived from testing each compound in the 86Rb+ Efflux Assay described below are provided in parentheses at the end of each Example. For example, the compound of Example 1 had an IC50 of 0.052 µM in the 86Rb+ Efflux Assay.
-
- To a solution of 1-[2-(4-nitrophenyl)ethyl]piperazine hydrochloride (30 mg, 0.11 mmol) in DMF (2 mL) was added 1-(2-bromoethyl)-4-nitrobenzene (31 mg, 1.3 mmol) and TEA (46 uL, 0.33 mmol). The mixture was heated to 80 °C for 16 hours. LC showed some desired product at that point. The desired 1,4-bis[2-(4-nitrophenyl)ethyl]piperazine was purified by mass-directed HPLC. LC-MS (IE, m/z): 385 [M+ 1]+. (0.052 µM)
-
- To a flask charged with 1-[2-(6-nitropyridin-3-yl)ethyl]piperazine hydrochloride (40 mg, 0.15 mmol) and and a stir bar was added 1-(2-bromoethyl)-4-nitrobenzene (40 mg, 0.18 mmol), DMF (2 mL), and triethylamine (0.082 mL, 0.59 mmol). The mixture was heated to 60 °C for 16 hours. LC showed formation of the desired product, which was separated by mass-directed HPLC. LC-MS (IE, m/z): 386 [M + 1]+. (0.28 µM)
-
- A mixture of 6-piperazin-1-yl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (generated from treateding tert-Butyl 4-(6-cyano-1, 2, 3, 4-tetrahydronaphthalen-2-yl)piperazine-1-carboxylate (110 mg, 0.32 mmol) with trifluoroacetic acid (2 ml, 26 mmol) at RT), 1-(2-bromoethyl)-4-nitrobenzene (47 mg, 0.21 mmol), and Hunig's Base (0.054 ml, 0.31 mmol in 1 ml DMF was stirred at 60 °C for 21 hours. The reaction was shaken with 1 ml 1 N NaOH and 1mL DCM. The organic layer was separated and evaporated to dryness. The residue was purified by mass directed HPLC to yield 6-{4-[2-(4-nitrophenyl)ethyl]piperazin-1yl}-5, 6, 7, 8-tetrahydronaphthalene-2-carbonitrile. LC-MS (IE, m/z): 391 [M + 1]+. (0.050 µM)
-
- A solution of 1-[2-(4-nitrophenyl)ethyl]piperazine (300mg, 1.3 mmol), 1-bromo-4-(2-bromoethyl)benzene (400mg, 1.5 mmol), and triethylamine (0.89 mL, 6.4 mmol) in DMF (5 mL) was heated to 60 °C for 16 hours. LC showed formation of the desired product. The desired product was purified by silica gel chromatography (10% MeOH in EtOAc). LC-MS (IE, m/z): 420 (M+1)+.
- A solution of 1-[2-(4-bromophenyl)ethyl]-4-[2-(4-nitrophenyl)ethyl]piperazine (100mg, 0.24 mmol), Zinc cyanide (84mg, 0.72 mmol), and tetrakis(triphenylphosphine)palladium in DMF (1 mL) was heated to 85 °C for 1 hour. LC showed formation of the desired product, which was separated by mass-directed HPLC. LC-MS (IE, m/z): 365 (M+1)+. (0.079 µM)
-
- A mixture of 2-(fluoromethyl)piperazine diacetate (30mg, 0.17 mmol), 1-(2-bromoethyl)-4-nitrobenzene (150mg, 0.67 mmol), tetrabutylammonium iodide (6.2 mg, 0.017 mmol), and K2CO3 (58 mg, 0.42 mmol) in DMF (2 mL) was heated to 60 °C for 16 hours. LC showed formation of the desired product, which was separated by mass-directed HPLC. LC-MS (IE, m/z): 417 (M+1)+. (0.18 µM)
-
- Hunig's Base (3.0 ml, 17 mmol) was added to a stirred solution of piperazine (250 mg, 2.9 mmol) and 1-bromo-4-(2-bromoethyl) benzene (0.89 ml, 5.8 mmol) at 50 °C for 16 hours. The reaction was then poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated and dried over Na2SO4 and evaporated to dryness. The residue was purified thru 40 gram ISCO Redi-sep column and eluted with 0-5% MeOH in DCM to give yellow solids of 1,4-bis[2-(4-bromophenyl)ethyl]piperazine (0.88 g, 1.95 mmol). LC-MS (IE, m/z): 453 [M + 1]+.
- Tetrakis(triphenylphosphine)palladium (15 mg, 0.013 mmol), zinc cyanide (52 mg, 0.44 mmol), and 1,4-bis[2-(4-bromophenyl)ethyl]piperazine (100 mg, 0.22 mmol) were stirred in microwave tube containing 2 ml DMF then microwaved at 80 °C for 1 hour. LC-MS showed product peak at 2.1 (M+1= 345) and also the mono cyano at 2.5 (M+1= 400). Added more Zn(CN)2 (52 mg, 0.44 mmol) and microwaved for another 1hour. The reaction mixture was cooled and filtered. To the filtrate was added 1 N NaOH then extracted with ethyl acetate. The organic layer was then washed with brine then dried over MgSO4 and evaporated to dryness. The residue was purified by prep TLC plate using 2.5% (NH4OH :MeOH 1:9) in DCM. The major spot isolated was 4,4'-(piperazine-1,4-diyldiethane-2,1-diyl)dibenzonittile. LC-MS (IE, m/z): 345 [M + 1]+. (0.79 µM)
-
- To a flask charged with 2-methyl-1-[2-(4-nitrophenyl)ethyl]piperazine hydrochloride (40 mg, 0.14 mmol) and a stir bar was added 1-(2-bromoethyl)-4-nitrobenzene (65 mg, 0.28 mmol), tetrabutylammonium iodide (5.2 mg, 0.014 mmol), K2CO3 (48 mg, 0.35 mmol), and DMF (2 mL). The mixture was heated to 80 °C for 16 hours. LC showed formation of the desired product, which was separated by mass-directed HPLC. LC-MS (IE, m/z): 399 [M+1]+. (0.14 µM)
-
- To a cooled solution of tert-butyl diallylcarbamate (145 mg, 0.74 mmol) in DCM (15 mL) at -78 °C was bubbled ozone for about 5 minutes. The solution was light blue at that point. Excess ozone was removed by flushing nitrogen through the reaction. To the reaction was added methyl (2S)-2-amino-3-(4-nitrophenyl)propanoate hydrochloride and triethylamine (74 mg, 0.74 mmol), followed by NaB(OAc)3H (940 mg, 4.4 mmol). The reaction was allowed to warm to RT, and stir for an additional 4 hours. The mixture was poured into water, extracted with DCM. The organic layer was washed with brine, dried with MgSO4, and purified by prep-TLC (50% EtOAc and Hexanes) to afford 93 mg of the desired tert-butyl 4-[(1S)-2-methoxy-1-(4-nitrobenzyl)-2-oxoethyl]piperazine-1-carboxylate. LC-MS (IE, m/z): 394 [M+1]+.
- The above material was further treated with 4N HCl in dioxane to remove the Boc group. The crude methyl (2S)-3-(4-nitrophenyl)-2-piperazin-1-ylpropanoate hydrochloride was used directly in the next step.
- A mixture of methyl (2S)-3-(4-nitrophenyl)-2-piperazin-1-ylpropanoate hydrochloride (100 mg, 0.30 mmol), 1-(2-bromoethyl)-4-nitrobenzene (77 mg, 0.33 mmol), and triethylamine (92 mg, 0.91 mmol) in DMF was heated to 60 °C for 16 hours. LC showed some product. More 1-(2-bromoethyl)-4-nitrobenzene (77 mg, 0.33 mmol) and triethylamine (92 mg, 0.91 mmol) were added to the reaction, and the mixture was allowed to heat for another 24 hours. LC showed complete reaction at that point. The reaction was diluted with EtOAc, washed with water, and purified by HPLC to deliver the desired product. LC-MS (IE, m/z): 443 [M+1]+. (0.51 µM)
-
- A mixture of 2,2-dimethylpiperazine (35mg, 0.31 mmol), 1-(2-bromoethyl)-4-nitrobenzene (280mg, 1.2 mmol), tetrabutylammonium iodide (11 mg, 0.031 mmol), and K2CO3 (169 mg, 1.2 mmol) in DMF (2 mL) was heated to 60 °C for 16 hours. LC showed formation of the desired product, which was separated by mass-directed HPLC. LC-MS (IE, m/z): 413 [M+1]+. (0.21 µM)
-
- A mixture of (1S,4S)-2,5-diazabicyclo[2.2.1]heptane dihydrobromide (60 mg, 0.23 mmol), 1-(2-bromoethyl)-4-nitrobenzene (210mg, 0.92 mmol), tetrabutylammonium iodide (8.5 mg, 0.023 mmol), and K2CO3 (128 mg, 0.92 mmol) in DMF (2 mL) was heated to 60 °C for 16 hours. LC showed formation of the desired product, which was separated by mass-directed HPLC. LC-MS (IE, m/z): 397 [M+1]+. (0.11 µM)
-
- A mixture of 2-cyclopropyl piperazine (50 mg, 0.40 mmol), 1-(2-bromoethyl)-4-nitrobenzene (360 mg, 1.6 mmol), tetrabutylammonium iodide (15 mg, 0.16 mmol), and K2CO3 (220 mg, 1.6 mmol) in DMF (2 mL) was heated to 60 °C for 16 hours. LC showed formation of the desired product, which was separated by mass-directed HPLC. LC-MS (IE, m/z): 425 [M+1]+. (0.86 µM)
-
- A mixture of 2-Difluoromethyl Piperazine (80 mg, 0.41 mmol), 1-(2-bromoethyl)-4-nitrobenzene (373 mg, 1.6 mmol), tetrabutylammonium iodide (15 mg, 0.16 mmol), and K2CO3 (220 mg, 1.6 mmol) in DMF (2 mL) was heated to 80 °C for 2 days. LC showed formation of the desired product, which was separated by mass-directed HPLC. LC-MS (IE, m/z): 435 [M+1]+. (0.44 µM)
-
- A mixture of 2-(tert-butoxymethyl)piperazinediium diacetate (60 mg, 0.26 mmol), 1-(2-bromoethyl)-4-nitrobenzene (240 mg, 1.0 mmol), tetrabutylammonium iodide (10 mg, 0.026 mmol), and K2CO3 (140 mg, 1.0 mmol) in DMF (2 mL) was heated to 80 °C for 16 hours. LC showed formation of the desired product, which was separated by mass-directed HPLC. LC-MS (IE, m/z): 471 [M+1]+.
- To a solution of 2-(tert-butoxymethyl)-1,4-bis[2-(4-nitrophenyl)ethyl]piperazine (30mg) in DCM (2 mL) was added TFA (2 mL). The reaction was allowed to stir at 25 °C for 2 hours. LC showed complete removal of the tert-butyl group. The solvents were removed under reduced pressure, and the residue was collected without further purification. LC-MS (IE, m/z): 415 [M+1]+. (0.26 µM)
-
- EDC (113 mg, 0.591 mmol) was added to a solution of 2-(4-nitrophenyl) propionic acid (92 mg, 0.473 mmol), Hunig'sBase (0.083 ml, 0.473 mmol) and 1-[2-(4-Nitrophenyl)ethyl]piperazine hydrochloride (107 mg, 0.394 mmol) in 5 ml DCM and stirred at room temperature for 3 hours. The crude mixture was diluted with ethyl acetate and washed with saturated solution of NH4Cl, brine, dried over sodium sulfate, filtered and concentrated. Residue was purified by prep-TLC plate with 5% (NH4OH:MeOH 9:1) in DCM to yield 1-[2-(4-nitrophenyl)ethyl]-4-[2-(4-nitrophenyl)propanoyl]piperazine (100 mg, 0.24 mmol). 1H-NMR (500 MHz, DMSO) δ ppm 8.19 (d, J=9 Hz, 2H), 8.11 (d, J= 9Hz, 2H), 7.54( d, J= 9.Hz, 2H), 7.48(d, J= 9.Hz, 2H), 4.33 (q, 1H), 3.39-3.48(m, 3H), 3.26-3.42 9m, 2H), 2.82( t, J= 7.0 Hz, 2H), 2.5 (b, 1H), 2.35-2.40( m, 2H), 2.26 (b, 1H), 2.0 (b, 1H), 1.30(d, J= 7Hz, 3H).
- Borane tetrahydrofuran complex 1M (0.714 ml, 0.714 mmol) was added to a stirred solution of 1-[2-(4-nitrophenyl)ethyl]-4-[2-(4-nitrophenyl)propanoyl] piperazine (92 mg, 0.22 mmol) in THF then refluxed for 1 hr. LC-MS and TLC showed starting material left. More borane-THF complex 1M (0.71 ml, 0.71 mmol) was added to the reaction and refluxed for 5 hrs. The reaction was cooled and added 6N HCl and then warmed to 65°C for 0.5 hour. The reaction was poured into 1N NaOH and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine then dried and concentrated. The residue was purified by mass directed HPLC. LC-MS (IE, m/z): 399 [M + 1]+. (0.34 µM)
-
- To a flask charged with 1-allyl-4-nitro-2-(trifluoromethyl)benzene (1.0g, 3.7 mmol) and a stir bar was added tetrakis(triphenylphosphine)palladium (214 mg, 0.18 mmol), Allyl Tri-n-butyltin (1.5 mL, 4.4 mmol), LiCl (470 mg, 11 mmol), and toluene (30 mL). The reaction was heated to 125 °C for 16 hours under an atmosphere of nitrogen. TLC showed complete reaction at that point. The product was purified by MPLC (Hexane:EtOAc) to furnish a light yellow oil. 1H-NMR (500 MHz, CDCl3) δ ppm 8.53 (m, 1H), 8.35 (m, 1H), 7.60 (d, J = 8.5Hz, 1H), 5.95 (m, 1H), 5.23 (d, J= 10Hz, 1H), 5.17 (d, J= 17Hz, 1H), 3.69 (m, 2H).
- A solution of 1-Allyl-4-nitro-2-(trifluoromethyl)benzene (300 mg, 1.3 mmol) in DCM (10 mL) and MeOH (30 mL) was treated with ozone at -78 °C. When the solution turned blue, triphenylphosphine (680 mg, 2.6 mmol) was added to the reaction, and it was allowed to warm up slowly. The desired aldehyde was purified by silica gel chromatography (Hexane:EtOAc). To the aldehyde (17 mg, 0.074 mmol) obtained above was added 1-[2-(4-nitrophenyl)ethyl]piperazine hydrochloride (20 mg, 0.074 mmol), Titanium (IV) isopropoxide (0.22 mL, 0.74 mmol), and sodium cyanoborohydride (46 mg, 0.74 mmol). The mixture was allowed to stir at RT for 10 minutes before ethanol (2 mL) was added to the reaction. LC showed formation of the desired product within 2 hours. The reaction was diluted with EtOAc, washed with brine, dried over sodium sulfate, concentrated and purified by mass-directed HPLC (0.1% TFA in water and acetonitrile). LC-MS (IE, m/z): 453 [M+1]+. (0.44 µM)
-
- A mixture of 3,8-diazabicyclo[3.2.1]octane (55mg, 0.49 mmol), 1-(2-bromoethyl)-4-nitrobenzene (340 mg, 1.5 mmol), tetrabutylammonium iodide (18 mg, 0.049 mmol), and K2CO3 (270 mg, 2.0 mmol) in DMF (2 mL) was heated to 80 °C for 16 hours. LC showed formation of the desired product, which was separated by mass-directed HPLC. LC-MS (IE, m/z): 411 [M+1]+. (0.19 µM)
-
- Titanium(IV) isopropoxide (1.8 ml, 6.0 mmol) was added to a mixture of 1-[2-(4-nitrophenyl)ethyl]piperazine hydrochloride (0.82 g, 3.0 mmol) and 2,1,3-benzodiazole-5-yl acetaldehyde (0.49 g, 3mmol) in ethanol (5 ml) then added sodium cyanoborohydride (0.75 g, 12.0 mmol) and 2 drops of acetic acid. The reaction was stirred at room temperature for 16 hours. The reaction mixture was filtered and poured into 1N NaOH then extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated. The residue was first purified by prep-TLC plate using 5% (1:9 NH4OH: MeOH) in DCM then repurified with mass-directed HPLC to yield 5-(2-{4-[2-(4-nitrophenyl) ethyl]piperazin-1-yl}ethyl)-2,1,3-benzoxadiazole. LC-MS (IE, m/z): 382 [M + 1]+. 1H-NMR (500 MHz, DMSO) δ ppm 8.19 (d, J=8.7 Hz, 2H), 8.03 (d, J = 9.2Hz, 1H), 7.90 (2,1H), 7.56(d, J=2.2 Hz, 2H), 7.54(d, J = 1.0 Hz, 1H), 3.04-3.65 (b, 16H). (0.17 µM)
-
- 4-Nitrophenylacetone (33 mg, 0.18 mmol) and 1-[2-(4-nitrophenyl)ethyl]piperazine hydrochloride (50 mg, 0.18 mmol) were added to Titanium(IV) Isopropoxide (110 µl, 0.37 mmol) and stirred for 1 hour. Ethanol was added followed by sodium cyanoborohydride (23 mg, 0.37 mmol) and stirred at room temperature overnight. Poured into 1N NaOH and extracted with ethyl acetate then washed with brine, dried and evaporated to dryness. The residue was purified by mass directed HPLC to yield 1-[2-(4-nitrophenyl)ethyl]-4-[1-(4-nitrophenyl)propan-2-yl]piperazine. LC-MS (IE, m/z): 399 [M + 1]+. 1H-NMR (500 MHz, DMSO) δ ppm 8.19 (t, J=8.5 Hz, 4H), 7.56 (d, J = 9.7Hz, 2H), 7.54(d, J = 9.7Hz, 2H), 2.76-4.4 (m, 15H), 1.02(d, J = 6.1Hz, 3H). (0.24 µM)
-
- 4-Nitrophenylacetone (208 mg, 1.161 mmol) was added to piperazine (50 mg, 0.58 mmol) and titanium(iv) isopropoxide (0.68 ml, 2.3 mmol) then stirred for 1 hour. Added ethanol (2 ml) and sodium cyanoborohydride (146 mg, 2.3 mmol) then stirred overnight. Poured into 1N NaOH and extracted with ethyl acetate then washed with brine, dried and evaporated to dryness. The residue was purified by mass directed HPLC to yield 1,4-bis [1-(4-nitrophenyl)propan-2-yl]piperazine. LC-MS (IE, m/z): 413 [M + 1]+. 1H-NMR (500 MHz, DMSO) δ ppm 8.199 (d, J=8.5 Hz, 4H), 7.55 (d, J = 8.9Hz, 4H), 3.41 (b,6H), 3.20 (b, 2H), 3.01 (b, 4H), 2.82 (t, J = 10.72Hz, 2H), 1.043 (d, J=6.11,6 H). (0.33 µM)
-
- To a flask charged with tert-butyl 2,5-diazabicyclo[2.2.2]octane-2-carboxylate (200 mg, 0.94 mmol) and a stir bar was added TFA (5 mL). The mixture was allowed to stir at RT for 2 hours. The volatiles were removed under reduced pressure. To the residue was added 1-(2-bromoethyl)-4-nitrobenzene (650 mg, 2.8 mmol), tetrabutylammonium iodide (35 mg, 0.094 mmol), K2CO3 (521 mg, 3.8 mmol), and DMF (5 mL). The mixture was heated to 80 °C for 16 hours. LC showed formation of the desired product, which was separated by mass-directed HPLC. LC-MS (IE, m/z): 411 [M+1]+. (0.21 µM)
-
- To a suspension of methyl piperazin-2-ylacetate (0.40 g, 1.73 mmol) in DMF (2.5 mL) was added 1-(2-bromoethyl)-4-nitrobenzene (1.0 g, 4.3 mmol), tetrabutyl ammonium iodide (cat.) and potassium carbonate (1.20 g, 8.7 mmol). The mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3x). The combined organics were washed with water (2x) and brine, then dried (Na2SO4), filtered and concentrated. The desired methyl {1,4-bis[2-(4-nitrophenyl)ethyl]piperazin-2-yl}acetate was purified by mass-directed HPLC. LC-MS (IE, m/z): 456.2 [M + 1]+. (0.39 µM)
-
- To a stirred solution of 4-bromo-2-methoxybenzonitrile (1.0 g, 4.7 mmol) in 30 mL of anhydrous THF was added BuLi (1.6 M, 3.3 mL, 5.2 mmol) dropwise at -78 °C under nitrogen atmosphere. After the addition, the pale red solution was stirred for 5 min at -78 °C and dry DMF (0.6 mL) then added dropwise. After 20 min, the reaction mixture was poured onto a saturated solution of sodium chloride (50 mL). The organic phase was separated, extracted with diethyl ether (100 mL), dried over Na2SO4 and distilled off the solvent to afford 4-formyl-2-methoxybenzonitrile. MS m/z: 162 (M+1)+.
- A mixture of 4-formyl-2-methoxybenzonitrile (383 mg, 2.38 mmol) and chloroacetic acid ethyl ester (291 mg, 2.38 mmol) were dissolved in 10 mL of dry benzene. Freshly prepared EtONa (3.09 mmol) in 2.5 mL of ethanol was added, and the mixture were stirred at room temperature for 2 hours. The mixture was added water, then extracted with EtOAc. The organic layers were dried over Na2SO4 and concentrated to afford ethyl 3-(4-cyano-3-methoxyphenyl)oxirane-2-carboxylate. MS m/z: 248 (M+1)+.
- A solution of ethyl 3-(4-cyano-3-methoxyphenyl)oxirane-2-carboxylate (400 mg, 1.6 mmol) in 5 mL of dry ethanol was cooled to 0 °C. Freshly prepared EtONa (2.1 mmol) in 4 mL of ethanol was added and stirred at 0 °C for 10 min. Then dropwise addition of 0.1 g of water, stirred at 0 °C for 2 hours, and the sodium salt of the epoxy compound was filtered. The sodium salt of the epoxy compound was then dissolved in 10 mL of water and added 10 mL of 1 N of HCl and 20 mL of toluene. The mixture was heated to reflux for 2 hours. The organic phase was separated, washed by saturated sodium chloride, dried over Na2SO4 and distilled off solvent to afford crude 2-methoxy-4-(2-oxoethyl)benzonitrile. MS m/z: 176 (M+1)+.
- A solution of 2-methoxy-4-(2-oxoethyl)benzonitrile (100 mg, 0.57 mmol), 1-[2-(4-Nitrophenyl)ethyl]piperazine (134 mg, 0.51 mmol) in 60 mL of dry methanol were added 2 drop of HOAc and then stirred at room temperature for 1 hr. Then NaBH(OAc)3 (362 mg, 1.71 mmol) was added an the then the mixture was stirred overnight. Concentrated and the residue was purified via prep-TLC to give 2-methoxy-4-(2-{4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl}ethyl)benzonitrile. 1H-NMR (300 MHz, CDCl3) δ ppm 8.14 (d, J=8.6 Hz, 2H), 7.35~7.47 (m, 3H), 6.79~6.85 (m, 2H), 3.12 (s, 3H), 2.48~2.96 (m, 16H). MS m/z: 395 (M+1)+. (0.052 µM)
-
- To a stirred solution of 4-bromo-3-methylbenzonitrile (4.0 g, 20 mmol) in 100 mL of anhydrous THF was added BuLi (1.6 M, 12.8 mL) dropwise at -78 °C under nitrogen atmosphere. After the addition, the pale red solution was stirred for 5 min at -78 °C and dry DMF (2.2 mL) then added drop wise. After 20 min, the reaction mixture was poured onto a saturated solution of sodium chloride (100 mL). The organic phase was separated, extracted with diethyl ether (100 mL), dried over Na2SO4 and distilled off the solvent to afford 3.5 g of crude 4-formyl-3-methylbenzonitrile. MS m/z: 146 (M+1)+,
- A mixture of 4-formyl-3-methylbenzonitrile (1.5 g, 10.3 mmol) and chloroacetic acid ethyl ester (1.2 g, 10 mmol) were dissolved in 60 mL of dry benzene. Freshly prepared EtONa (12.4 mmol) in 8 mL of ethanol was added, and the mixture were stirred at room temperature for 2 hours. The mixture was added water, then extracted with EA, dried over Na2SO4 and distilled off solvent to afford 1.7 g of crude ethyl 3-(4-cyano-2-methylphenyl)oxirane-2-carboxylate. MS m/z: 232 (M+1)+.
- A solution of ethyl 3-(4-cyano-2-methylphenyl)oxirane-2-carboxylate (927 mg, 4.0 mmol) in 10 mL of dry ethanol was cooled to 0 °C. Freshly prepared EtONa (12.4 mmol) in 8 mL of ethanol was added and stirred at 0 for 10 min. Then dropwise addition of 0.1 g of water, stirred at 0 °C for 2 hours, and the sodium salt of the epoxy compound was filtered. The sodium salt of the epoxy compound was then dissolved in 5 mL of water and added 5 mL of 1 N of HCl and 20 mL of toluene. The mixture was heated to reflux for 2 hours. The organic phase was separated, washed by saturated sodium chloride, dried over Na2SO4 and distilled off solvent to afford 130 mg of crude 3-methyl-4-(2-oxoethyl)benzonitrile. MS m/z: 160 (M+1)+.
- A mixture of 3-methyl-4-(2-oxoethyl)benzonitrile (130 mg, 0.8 mmol), 1-[2-(4-nitrophenyl)ethyl]piperazine (188 mg, 0.8 mmol) and NaBH(OAc)3 in 25 mL of dry methanol were stirred at room temperature over night. The solid was filtered to get 160 mg of 3-methyl-4-((E)-2-{4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl}vinyl)benzonitrile. 1H-NMR (300 MHz, CDCl3) δ ppm 8.15 (d,J=8.6 Hz, 2H), 7.31~7.40 (m, 5H), 6.72 (d, J=13.5Hz, 1H), 5.35 (d, J=13.9Hz, 1H), 3.20 (s, 4H), 2.95 (s, 2H), 2.57~2.75 (m, 6H), 2.26 (s, 3H). MS m/z: 377 (M+1)+,
- A solution of 3-methyl-4-((E)-2-{4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl}vinyl)benzonitrile (100 mg, 0.24 mmol) in 15 mL of methanol and 10 mL of DCM was added NaBH4 (508 mg, 2.4 mmol), then stirred at room temperature overnight. The crude product was purified via prepare TLC (methanol/DCM 1:10) to give 3-methyl-4-(2-{4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl}ethyl)benzonitrile. 1H-NMR (300 MHz, CDCl3) δ ppm 8.12 (d, J=8.6 Hz, 2H), 7.23~7.40 (m, 5H), 3.01~3.21 (m, 2H), 2.80~2.92 (m, 4H), 2.50~2.65 (m, 10H), 2.33 (s, 3H). MS m/z: 379 (M+1)+. (0.062 µM)
-
- To a stirred solution of 4-bromo-2-methylbenzonitrile (4.0 g, 20 mmol) in 100 mL of anhydrous THF was added BuLi (1.6 M, 12.8 mL) dropwise at -78 °C under nitrogen atmosphere. After the addition, the pale red solution was stirred for 5 min at -78 °C and dry DMF (2.2 mL) then added dropwise. After 20 min, the reaction mixture was poured onto a saturated solution of sodium chloride (100 mL). The organic phase was separated, extracted with diethyl ether (100 mL), dried over Na2SO4 and distilled off the solvent to afford 4-formyl-2-methylbenzonitrile. MS m/z: 146 (M+1)+.
- A mixture of 4-formyl-2-methylbenzonitrile (1.5 g, 10.3 mmol) and chloroacetic acid ethyl ester (1.2 g, 10 mmol) were dissolved in 60 mL of dry benzene. Freshly prepared EtONa (12.4 mmol) in 5 mL of ethanol was added, and the mixture was stirred at room temperature for 2 hours. The mixture was added water, then extracted with EtOAc. The organic layers were dried over Na2SO4 and concentrated to afford ethyl 3-(4-cyano-3-methylphenyl)oxirane-2-carboxylate. MS m/z: 232 (M+1)+.
- A solution of 3-(4-cyano-3-methylphenyl)oxirane-2-carboxylate (927 mg, 4.0 mmol) in 5 mL of dry ethanol was cooled to 0 °C. Freshly prepared EtONa (5 mmol) in 4 mL of ethanol was added and stirred at 0 °C for 10 min. Then dropwise addition of 0.1 g of water, stirred at 0 °C for 2 hours, and the sodium salt of the epoxy compound was filtered. The sodium salt of the epoxy compound was then dissolved in 5 mL of water and added 5 mL of 1 N of HCl and 20 mL of toluene. The mixture was heated to reflux for 2 hours. The organic phase was separated, washed by saturated sodium chloride, dried over Na2SO4 and distilled off solvent to afford crude 2-methyl-4-(2-oxoethyl)benzonitrile. MS m/z: 160 (M+1)+.
- A solution of 2-methyl-4-(2-oxoethyl)benzonitrile (130 mg, 0.8 mmol), 1-[2-(4-nitrophenyl)ethyl]piperazine (190 mg, 0.8 mmol) in 25 mL of dry methanol were added 2 drop of HOAc and then stirred at room temperature for 1 hr. Then NaBH(OAc)3 (380 mg, 1.8 mmol) was added an the then the mixture was stirred overnight. Concentrated and the residue was purified via prep-TLC to give 2-Methyl-4-(2-{4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl}ethyl)benzonitrile. 1H-NMR (300 MHz, CDCl3) δ ppm 8.15 (d, J=8.6 Hz, 2H), 7.36-7.53 (m, 3H), 7.12 (t, J=9.4 Hz, 2H), 2.65~2.97 (m, 16H), 2.52 (s, 3H). MS m/e: 379 (M+1)+. (0.19 µM)
-
- A mixture (6S)-6-piperazin-1-yl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (0.31 mg, 0.13 mmol), 1-(2-bromoethyl)-4-nitrobenzene (80 mg, 0.35 mmol), and triethylamine (0.15 mL, 1.1 mmol) in DMF was heated to 60 °C for 30 hours. LC showed formation of the desired product. The reaction was diluted with EtOAc, washed with water and brine, dried over MgSO4, and purified by MPLC to deliver 13 mg of (6S)-6-{4-[2-(4-nitrophenyl)ethyl]piperazin-l-yl}-5,6,7,8-tetrahydronaphthalene-2-carbonitrile. LC-MS (IE, m/z): 391 [M+1]+. (0.083 µM)
-
- (6R)-6-{4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl}-5,6,7,8-tetrahydronaphthalene-2-carbonitrile Was prepared following the same procedure of EXAMPLE 25 from (6R)-6-piperaz-in-1-yl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile. LC-MS (IE, m/z): 391 [M+1]+. (0.066 µM)
-
- To a flask charged with 5-(2-piperazin-1-ylethyl)-2,1,3-benzoxadiazole hydrochloride (25 mg, 0.093 mmol) and a stir bar was added 6-(1H-tetrazol-1-yl)-3,4-dihydronaphthalen-2(1H)-one (30 mg, 0.14 mmol), Titanium (IV) isopropoxide (0.27 mL, 0.93 mmol), and sodium cyanoborohydride (29 mg, 0.46 mmol). The mixture was allowed to stir for 3 hours. LC showed formation of the desired product. The reaction was diluted with EtOAc, washed with brine, dried over sodium sulfate, filtered, concentrated and purified by mass-directed HPLC (0.1% TFA in water and acetonitrile). LC-MS (IE, m/z): 431 [M+1]+. (0.98 µM)
-
- A mixture of 4-bromo-2,6-difluorobenzonitrile (2.0 g, 9.2 mmol), allyl-tributyl-stannane (3.65 g, 11.0 mmol), LiCl (1.17 mg, 28 mmol) and Pd(PPh)4 (0.2 g) in 70 mL of anhydrous toluene was refluxed under N2 overnight Checked the reaction with TLC and concentrated under reduced pressure. The residue was purified by silica gel cloumn chromatography to give the product 4-allyl-2,6-difluorobenzonittile. MS m/z: 180 (M+1)+.
- To a solution of 4-allyl-2,6-difluorobenzonitrile (1.7 g, 9.2 mmol) in 30 mL of methanol and 10 mL of water was added OsO4 (210 mg) and NMO (3.11 g, 23 mmol), and the mixture was stirred at ambient temperature overnight. Remove the methanol under reduced pressure, the residue was dissolved in EtOAc, washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by fast column chromatograph to give 4-(2,3-dihydroxypropyl)-2,6-difluorobenzonitrile. MS m/z: 214 (M+1)+.
- A solution of 4-(2,3-dihydroxypropyl)-2,6-difluorobenzonitrile (500 mg, 2.4 mmol) in 10 mL of methanol and 3 mL of water was cooled to 0 °C by ice bath, then NaIO4 (754 mg, 3.5 mmol) was added and the mixture was stirred at 0 °C for two hours. The reaction was monitored according to TLC. The mixture was filtered and concentrated. The residue was dissolved in DCM, dried over anhydrous sodium sulfate, and then purified by flash column chromatography to give 2,6-difluoro-4-(2-oxoethyl)benzonitrile. MS m/z: 182 (M+1)+.
- A solution of 2,6-difluoro-4-(2-oxoethyl)benzonitrile (185 mg, 1.0 mmol), 1-[2-(4-nitrophenyl)ethyl]piperazine (200 mg, 0.85 mmol) and NaBH(OAc)3 (720 mg, 3.4 mmol) in anhydrous DCM (10 mL) was stirred at ambient temperature overnight. The reaction was completed according to TLC. The reaction mixture was added 20 mL of DCM, washed with brine, separated the organic layer, dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative TLC to give the product. 1H-NMR (400 MHz, CDCl3) δ ppm 8.15-8.17 (d, J=8.6 Hz, 2H), 7.37~7.39 (d, J=8.6 Hz, 2H), 6.92~6.94 (d, J=8.6 Hz, 2H), 2.54~3.11 (m,16H). MS m/z: 401 (M+1)+. (0.16 µM)
-
- To a 12 mL reaction vial was added 1-(2-bromoethyl)-4-nitrobenzene (42 mg, 0.18 mmol), 4-(5-cyano-2,3-dihydro-1H-inden-2-yl)piperazin-1-ium chloride (33 mg, 0.12 mmol) and acetonitrile (2 mL). To a stirred solution of above mixture was added N-ethyl-N-(propan-2-yl)propan-2-amine (32 mg, 0.24 mmol). The reaction was stirred at 60 °C for 5 hr, then concentrated and purified by preparative TLC to give the desired product. LC-MS (IE, m/z): 377 [M + 1]+. (0.73 µM)
-
- A mixture of 1-[2-(4-Nitrophenyl)ethyl]piperazine hydrochloride (50 mg, 0.18 mmol), 5-nitro-1,3-dihydro-2H-inden-2-one (39 mg, 0.22 mmol), sodium cyanoborohydride (58 mg, 0.92 mmol, and Titanium (IV) Isopropoxide (0.54 mL, 1.8 mmol) was allowed to stir at RT for 3 hours. LC showed formation of the desired product. The reaction was diluted with EtOAc, washed with brine, dried over sodium sulfate, filtered, concentrated and purified by mass-directed HPLC (0.1% TFA in water and acetonitrile). LC-MS (IE, m/z): 397 (M+1)+. (0.31 µM)
-
- A mixture of 4-bromo-3-methoxybenzonitrile (1.4 g, 6.7 mmol), allyl-tributyl-stannane (2.7 g, 8.1 mmol), LiCl (0.86 mg, 20 mmol) and Pd(PPh)4 (0.2 g) in 25 mL of anhydrous toluene was refluxed under N2 overnight. Checked the reaction with TLC and concentrated under reduced pressure. The residue was purified by silica gel cloumn chromatography to give the product 4-allyl-3-methoxybenzonitrile. MS m/z: 174 (M+1)+.
- To a solution of 4-allyl-3-methoxybenzonitrile (1.1 g, 6.4 mmol) in 30 mL of methanol and 10 mL of water was added OsO4 (140 mg) and NMO (2.2 g, 16 mmol), and the mixture was stirred at ambient temperature overnight. Remove the methanol under reduced pressure, the residue was dissolved in EtOAc, washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by fast column chromatograph to give 4-(2,3-dihydroxypropyl)-3-methoxybenzonitrile. MS m/z: 208 (M+1)+.
- A solution of 4-(2,3-dihydroxypropyl)-3-methoxybenzonitrile (500 mg, 2.6 mmol) in 10 mL of methanol and 3 mL of water was cooled to 0 °C by ice bath, then NaIO4 (830 mg, 3.9 mmol) was added and the mixture was stirred at 0 °C for two hours. The reaction was monitored according to TLC. The mixture was filtered and concentrated. The residue was dissolved in DCM, dried over anhydrous sodium sulfate, and then purified by flash column chromatography to give 3-methoxy-4-(2-oxoethyl)benzonitrile. MS m/z 176 (M+1)+.
- A solution of 3-methoxy-4-(2-oxoethyl)benzonitrile (91 mg, 0.56 mmol), 1-[2-(4-nitrophenyl)ethyl]piperazine (110 mg, 0.56 mmol) and NaBH(OAc)3 (393 mg, 1.87 mmol) in anhydrous DCM (15 mL) was stirred at ambient temperature overnight. The reaction was completed according to TLC. The reaction mixture was added 15 mL of DCM, washed with brine, separated the organic layer, dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative TLC to give the product. 1H-NMR (400 MHz, CDCl3) δ 8.15 (d, J=8.5Hz, 3H), 7.37 (d, J=8.5Hz, 3H), 7.05 (s, 1H), 3.85 (s, 3H), 2.85~2.96 (m, 5H), 2.49~2.75 (m, 11H). MS m/z: 395 (M+1)+. (0.30 µM)
-
- A mixture of 4-bromo-2-fluorobenzonitrile (250 mg, 1.3 mmol), allyl-tributyl-stannane (500 mg, 1.5 mmol), LiCl (160 mg, 3.8 mmol) and Pd(PPh)4 (15 mg) in 5 mL of anhydrous toluene was refluxed under N2 overnight. Checked the reaction with TLC and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the product 4-allyl-2-fluorobenzonitrile. MS m/z: 162 (M+1)+.
- To a solution of 4-allyl-2-fluorobenzonitrile (1.3 g, 8.1 mmol) in 30 mL of methanol and 10 mL of water was added OsO4 (200 mg) and NMO (2.7 g, 20 mmol), and the mixture was stirred at ambient temperature overnight. Remove the methanol under reduced pressure, the residue was dissolved in EtOAc, washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by fast column chromatograph to give 4-(2,3-dihydroxypropyl)-2-fluorobenzonitrile. MS m/z: 196 (M+1)+.
- A solution of 4-(2,3-dihydroxypropyl)-2-fluorobenzonitrile (500 mg, 2.6 mmol) in 10 mL of methanol and 3 mL of water was cooled to 0 °C by ice bath, then NaIO4 (820 mg, 3.8 mmol) was added and the mixture was stirred at 0 ° C for two hours. The reaction was monitored according to TLC. The mixture was filtered and concentrated. The residue was dissolved in DCM, dried over anhydrous sodium sulfate, and then purified by flash column chromatography to give 2-fluoro-4-(2-oxoethyl)benzonitrile. MS m/z: 164 (M+1)+.
- A solution of 2-fluoro-4-(2-oxoethyl)benzonitrile (140 mg, 0.88 mmol), 1-[2-(4-nitrophenyl)ethyl]piperazine (170 mg, 0.73 mmol) and NaBH(OAc)3 (620 mg, 2.9 mmol) in anhydrous DCM (10 mL) was stirred at ambient temperature overnight. The reaction was completed according to TLC. The reaction mixture was added 20 mL of DCM, washed with brine, separated the organic layer, dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative TLC to give the product. 1H-NMR (400 MHz, CDCl3) δ ppm 8.13-8.16 (d, J=8.6 Hz, 2H), 7.52~7.55 (t, J=6.6 Hz, 1H), 7.36-7.38 (d, J=8.6 Hz, 2H), 7.08~7.12 (m, 2H), 2.89~3.00 (m, 4H), 2.56~2.78 (m,12H). MS m/z: 383 (M+1)+. (0.24 µM)
-
- To a solution of 6-Piperazin-1-yl-5,6,7,8-tetrahydronaphtho[2,3-c][1,2,5]oxadiazole hydrochloride (20 mg, 0.068 mmol), 5-(2-bromoethyl)-2-benzofuran-1(3H)-one (33mg, 0.14 mmol), and tetrabutylammonium iodide (2.5 mg, 6.8 umol) in DMF (2 mL) was added triethylamine (0.028 mL, 0.20 mmol). The mixture was heated to 55 °C for 6 hours. LC showed formation of the desired product, which was separated by mass-directed HPLC. LC-MS (IE, m/z): 419 [M + 1]+. (0.21 µM)
-
- To a flask containing 1-(piperazin-1-ylmethyl)-2, 3-dihydro-1H-indene-4-carbonitrile (0.04 g, 0.17 mmol) was added 5-(2-bromoethyl)-2-benzofuran-1-(3H)-one (0.02 g, 0.06 mmol), tetrabutyl ammonium iodide (0.02 g, 0.06 mmol) and morpholine (0.08 mL, 0.99 mmol); the resulting mixture was dissolved in DMF (3 mL) and stirred at 60 °C. Analysis of the reaction mixture indicated that reaction had gone to completion. The solution was concentrated in vacuo and shot into Mass-directed HPLC for separation to give the desired 1-({4-[2-(3-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}methyl)indane-4-carbonitrile. LC-MS (IE, m/z): 402 [M + 1]+ (0.27 µM)
-
- To a mixture of 5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one methyl (29 mg, 0.10 mmol) and 2-methoxy-4-(2-oxoethyl)benzonitrile (15 mg, 0.085 mmol) in methanol (1.0 mL) at 0 °C was added sodium cyanoborohydride (7.5 mg, 0.12 mmol) and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated and purified by mass-directed HPLC to provide 2-methoxy-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile. LC-MS (IE, m/z): 405.2 [M + 1]+. 1H-NMR (500 MHz, CD3OD) δ ppm 7.86 (m,1H), 7.58 (overlapping m's, 3H), 7.13 (s, 1H), 7.02 (m, 1H), 5.38 (s, 2H), 3.98 (s, 3H), 3.37-3.21 (overlapping m's, 12H) 3.18 (m, 2H), 3.08 (m, 2H). (0.089 µM)
-
- To a 12 mL reaction vial was added 4-formyl-3,4-dihydro-2H-chromene-7-carbonitrile (50 mg, 0.27 mmol), 5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one (66 mg, 0.27 mmol) and dichloromethane (3 mL). The solution was stirred at RT under N2 for 10 min. To above solution was added sodium tris(acetoxy) borohydride (224 mg, 1.1 mmol). The reaction was stirred at RT for 18 hours under N2, extracted with DCM, washed with brine and water. The organic phase was dried over MgSO4, filtered and purified by flash column chromatography. LC-MS (IE, m/z): 418.1 [M + 1]+. 1H NMR (500 MHz, CDCl3, δ in ppm): 7.84 (1H, d, J= 7.8 Hz), 7.38 (1H, d, J= 7.8 Hz), 7.32 (2H, m), 7.11 (1H, dxd, J= 8.0 Hz, J= 1.6 Hz), 7.08 (1H, d, J= 1.6 Hz), 5.60 (2H, s), 4.4 (2H, m), 3.0 (4H, m), 2.4- 2.8 (10H, m), 2.0 (2H, m). (0.092 µM)
-
- To a 12 mL reaction vial was added 5-formyl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (50 mg, 0.27 mmol), 5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one (66 mg, 0.27 mmol) and dichloromethane (3 mL). The solution was stirred at RT under N2 for 10 min. To above solution was added sodium tris(acetoxy) borohydride (172 mg, 0.81 mmol). The reaction was stirred at RT for 18 hours under N2, extracted with DCM, washed with brine and water. The organic phase was dried over MgSO4, filtered and purified by flash column chromatography. LC-MS (IE, m/z): 416.2 [M + 1]+. (0.46 µM)
-
- To the 2-fluoro-4-(2-oxoethyl)benzonitrile (0.39 g, 2.4 mmol) were added dichloromethane (40 mL) and 5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride [(0.68 g, 2.4 mmol), in dichloromethane (3 mL), and triethylamine (0.67 mL, 4.8 mmol)], and the mixture was stirred at room temperature for 0.5 h. Sodium triacetoxyborohydride (2.53 g, 12 mmol) was added, and the reaction mixture was stirred at room temperature for 24 h. The reaction was quenched with water (5 mL), and the organics were extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL) and dried (MgSO4). Filtration followed by concentration afforded an oily residue, which was purified via mass-directed reverse-phase HPLC followed by evaporation and drying of the pure fraction obtained off white TFA salt foam which then converted to HCl salt by triturating in 1M HCl in diethyl ether (1 mL, 1 h). Evaporation and dried under vacuum provided the final product as an off white solid. LC-MS (IE, m/z): 394.24 [M + 1]+. (0.049 µM)
-
- 2,5-Difluoro-4-[2-[4-[2-(1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile was prepared in a similar fashion to that described for the synthesis of Example 38 starting from 5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride and 2,5-difluoro-4-(2-oxoethyl)benzonitrile. LC-MS (IE, m/z): 412.1 [M + 1]+. (0.23 µM)
-
- 2-Bromo-4-[2-[4-[2-(1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile was prepared in a similar fashion to that described for the synthesis of Example 38 starting from 5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride and 2-bromo-4-(2-oxoethyl)benzonitrile. LC-MS (IE, m/z): 456.0 [M + 1]+. (0.099 µM)
-
- 2-Methoxy-4-[2-[4-[2-(4-methyl-1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile was prepared in a similar fashion to that described for the synthesis of Example 38 starting from 4-methyl-5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride and 2-methoxy-4-(2-oxoethyl)benzonitrile. LC-MS (IE, m/z): 420.2 [M + 1]+. (0.035 µM)
-
- 5-[2-[4-[2-[6-(Tetrazol-1-yl)-3-pyridyl]ethyl]piperazin-1-yl]ethyl]-3H-isobenzofuran-1-one was prepared in a similar fashion to that described for the synthesis of Example 38 starting from 5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride and [6-(1H-tetrazol-1-yl)pyridin-3-yl]acetaldehyde. LC-MS (IE, m/z): 392.0 [(M + 1)+ - 28]. (0.91 µM)
-
- 4-Methyl-5-[2-[4-[2-[6-(tetrazol-1-yl)-3-pyridyl]ethyl]piperazin-1-yl]ethyl]-3H-isobenzofuran-1-one was prepared in a similar fashion to that described for the synthesis of Example 38 starting from 4-methyl-5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride and [6-(1H-tetrazol-1-yl)pyridin-3-yl]acetaldehyde. LC-MS (IE, m/z): 406.1 [(M + 1)+ - 28]. (0.61 µM)
-
- 2-Methoxy-4-[1-methyl-2-[4-[2-(1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile was prepared in a similar fashion to that described for the synthesis of Example 38 starting from 5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride and 2-methoxy-4-(1-oxopropan-2-yl)benzonitrile. LC-MS (IE, m/z): 420.5 [M + 1]+. (0.28 µM)
-
- 2-Mthoxy-4-[1-methyl-2-[4-[2-(4-methyl-1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile was prepared in a similar fashion to that described for the synthesis of Example 38 starting from 4-methyl-5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride and 2-methoxy-4-(1-oxopropan-2-yl)benzonitrile. LC-MS (IE, m/z): 434.5 [M + 1]+. (0.15 µM)
-
- 2-Methoxy-4-[2-[4-[2-(4-methyl-1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]propyl]benzonitrile was prepared in a similar fashion to that described for the synthesis of Example 38 starting from 4-methyl-5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride and 2-methoxy-4-(2-oxopropyl)benzonitrile. LC-MS (IE, m/z): 434.4 [M + 1]+. (0.19 µM)
-
- 4-[1,1-Dimethyl-2-[4-[2-(4-methyl-1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]-2-methoxy-benzonitrile was prepared in a similar fashion to that described for the synthesis of Example 38 starting from 4-methyl-5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride and 2-methoxy-4-(2-methyl-1-oxopropan-2-yl)benzonitrile. LC-MS (IE, m/z): 448.6 [M + 1]+. (0.30 µM)
-
- 2-Methoxy4-[2-[4-[2-(1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]propyl]benzonitrile was prepared in a similar fashion to that described for the synthesis of Example 38 starting from 5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride and 2-methoxy-4-(2-oxopropyl)benzonitrile. LC-MS (IE, m/z): 420.6 [M + 1]+. (0.21 µM)
-
- 2-(Difluoromethoxy)-4-[2-[4-[2-(4-methyl-1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile was prepared in a similar fashion to that described for the synthesis of Example 38 starting from 4-methyl-5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride and 2-(difluoromethoxy)-4-(2-oxoethyl)benzonitrile. LC-MS (IE, m/z): 456.5 [M + 1]+. (0.16 µM)
-
- To a 12 mL reaction vial was added 6-fluoro-4-formyl-3,4-dihydro-2H-chromene-7-carbonitrile (12 mg, 0.058 mmol), 5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one (14.4 mg, 0.058 mmol) and dichloromethane (3 mL). The solution was stirred at r.t. under N2 for 10 min. To above solution was added sodium triacetoxy borohydride (49.6 mg, 0.23 mmol). The reaction was stirred at RT for 18 hours under N2, extracted with DCM, washed with brine and water. The organic phase was dried over MgSO4, filtered and purified by flash column chromatography. LC-MS (IE, m/z): 436.3 [M + 1]+. (0.44 µM)
-
- To a solution of (1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (0.495 g, 2.8 mmol) and tert-butyl 3-(trifluoromethyl)piperazine-1-carboxylate (0.65 g, 2.6 mmol) in methanol (5 ml) at 0 °C was added sodium cyanoborohydride (0.21 g, 3.3 mmol) and the reaction stirred 12 hours at RT. The reaction mixture was concentrated and diluted with water. The aqueous was extracted with dichloromethane and the combined organics washed with brine, dried (MgSO4), filtered and concentrated. MPLC chromatography (2 → 20% EtOAc:hexane) provided tert-butyl 4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-3-(trifluoromethyl)piperazine-1-carboxylate. LC-MS (IE, m/z ): 415.1 [M + 1]+.
- To a solution of tert-butyl 4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-3-(trifluoromethyl)piperazine-1-carboxylate (183 mg, 0.44 mmol) in 1,4-dioxane (2 ml) was added 4 N HCl in dioxane (1 mL) and the reaction stirred at room temperature for 12 h. LC-MS shows product formation. The reaction mixture was concentrated in vacuo and dried under high vacuum to provide 5-{2-[2-(trifluoromethyl)piperazin-1-yl]ethyl}-2-benzofuran-1(3H)-one which was used directly without further purification. LC-MS (IE, m/z ): 194.2 [M + 1]+.
- To a mixture of 5-{2-[2-(trifluoromethyl)piperazin-1-yl]ethyl}-2-benzofuran-1(3H)-one (95 mg, 0.27 mmol) and 2-methoxy-4-(2-oxoethyl)benzonitrile (40 mg, 0.23 mmol) in methanol (1.0 mL) at 0 °C was added sodium cyanoborohydride (20 mg, 0.32 mmol) and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated and purified by mass-directed HPLC to provide 2-methoxy-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-3-(tri fluoromethyl)piperazin-1-yl}ethyl)benzonitrile. LC-MS (IE, m/z): 474.3 [M + 1]+. 1H-NMR (500 MHz, CD3OD) δ ppm 7.82 (m,1H) 7.60 (overlapping m's, 3H), 7.15 (s, 1H), 7.02 (m, 1H), 5.38 (s, 2H), 3.98 (s, 3H), 3.90 (m, 1H), 3.58 (m, 2H), 3.51 (m, 2H), 3.43 (m, 2H), 3.20 (m, 4H), 3.12 (m, 2H), 3.08 (m, 2H). (0.65 µM)
-
- To a mixture of 5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one (94 mg, 0.33 mmol) and 5-fluoro-2-methoxy-4-(2-oxoethyl)benzonitrile (58 mg, 0.30 mmol) in methanol (3.0 mL) at 0 °C was added sodium cyanoborohydride (29 mg, 0.47 mmol) and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated and purified by mass-directed HPLC to provide 5-fluoro-2-methoxy-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile. LC-MS (IE, m/z): 424.3 [M + 1]+. (0.068 µM)
-
- To a mixture of 5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one (95 mg, 0.27 mmol) and 5-fluoro-2-methoxy-4-(2-oxoethyl)benzonitrile (40 mg, 0.23 mmol) in methanol (1.0 mL) at 0 °C was added sodium cyanoborohydride (20 mg, 0.32 mmol) and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated and purified by mass-directed HPLC to provide 5-fluoro-2-methoxy-4-(2-{4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile. LC-MS (IE, m/z): 438.4 [M + 1]+. (0.034 µM)
-
- To a mixture of piperazine (13 mg, 0.15 mmol) and 5-fluoro-2-methoxy-4-(2-oxoethyl)benzonitrile (58 mg, 0.30 mmol) in methanol (3.0 mL) at 0 °C was added sodium cyanoborohydride (24 mg, 0.38 mmol) and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated and purified by mass-directed HPLC to provide 4,4'-(piperazine-1,4-diyldiethane-2,1-diyl)bis(5-fluoro-2-methoxybenzonitrile). LC-MS (IE, m/z): 441.4 [M+ 1]+. (0.34 µM)
-
- To a mixture of 4-methyl-5-[1-(piperazin-1-yl)propan-2-yl]-2-benzofuran-1(3H)-one (25 mg, 0.080 mmol) and 2-methoxy-4-(2-oxoethyl)benzonitrile (17 mg, 0.097 mmol) in methanol (1.0 mL) at 0 °C was added sodium cyanoborohydride (7 mg, 0.113 mmol) and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated and purified by mass-directed HPLC to provide 2-methoxy-4-(2-{4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)propyl]piperazin-1-yl}ethyl)benzonitrile. LC-MS (IE, m/z): 434.3 [M + 1]+. (0.17 µM)
-
- To a mixture of tert-butyl 3-(trifluoromethyl)piperazine-1-carboxylate (72 mg, 0.28 mmol) and 2-methoxy-4-(2-oxoethyl)benzonitrile (50 mg, 0.28 mmol) in methanol (2.5 mL) at 0 °C was added sodium cyanoborohydride (25 mg, 0.40 mmol) and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated and purified by column chromatography (4->30% ethyl acetate:hexanes) to provide tert-butyl 4-[2-(4-cyano-3-methoxyphenyl)ethyl]-3-(trifluoromethyl)piperazine-1-carboxylate. LC-MS (IE, m/z): 414.4 [M + 1]+.
- A solution of tert-butyl 4-[2-(4-cyano-3-methoxyphenyl)ethyl]-3-(trifluoromethyl)piperazine-1-carboxylate (116 mg, 0.282 mmol) in dichloromethane (2 mL) was treated with trifluoroacetic acid (1 mL) and stirred at room temperature for 2 hours. The reaction mixture was concentrated to provide 2-methoxy-4-{2-[2-(trifluoromethyl)piperazin-1-yl]ethyl}benzonitrile. LC-MS (IE, m/z): 314.4 [M + 1]+.
- To a mixture of 2-methoxy-4-{2-[2-(trifluoromethyl)piperazin-1-yl]ethyl}benzonitrite (116 mg, 0.28 mmol) and (1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (49 mg, 0.28 mmol) in methanol (1.0 mL) at 0 °C was added sodium cyanoborohydride (18 mg, 0.28 mmol) and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated and purified by mass-directed HPLC to provide 2-methoxy-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-2-(trifluoromethyl)piperazin-1-yl}ethyl)benzonitrile. LC-MS (IE, m/z): 474.4 [M + 1]+. (0.27 µM)
-
- To a flask containing 3-methyl-6-[2-(piperazin-1-yl)ethyl]-3,4-dihydro-1H-isochromen-1-one hydrochloride (123 mg, 0.40 mmol) was addedin 2mL of EtOH and NaOH (79 µl, 0.40 mmol). The solvent was removed and the free amine redissolved in DCM and filtered directly into a flask containing 2-methoxy-4-(2-oxoethyl)benzonitrile (58 mg, 0.33 mmol). The mixture was allowed to stir for 20 minutes before sodium triacetoxyborohydride (210 mg, 0.99 mmol) was added. The reaction stirred for 1 hour before being quenched with MeOH. The crude reaction was stirred an additional 30 minutes and the excess solvent was removed. The crude material was redissolved in DCM, filtered, concentrated and purified via MPLC [10-50% (10% MeOH in DCM)/DCM)] to afford 90mg (63% yield) of 2-methoxy-4-(2-{4-[2-(3-methyl-1-oxo-3,4-dihydro-1H-isochromen-6-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile. 1H NMR (500 MHz; DMSO): 7.80 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 7.22 (s, 1H), 7.14 (s, 1H), 6.95 (d, J = 7.8 Hz, 1H), 4.65 (m, 1H), 3.88 (bs, 4H), 2.94 (m, 4H), 2.78 (m, 4H), 2.43 (m, 4H), 1.38 (d, J= 6.8 Hz, 3H). LC-MS (IE, m/z): 375 [M+1]+. (0.098 µM)
-
- The desired product was synthesized according to the procedure described for Example 57, utilizing (3S)-6-(1,3-dioxolan-2-ylmethyl)-3-methyl-3,4-dihydro-1H-isochromen-1-one and (3S)-6-(1,3-dioxolan-2-ylmethyl)-3-methyl-3,4-dihydro-1H-isochromen-1-one as the starting components in the reaction. LC-MS (IE, m/z): 463 [M+1]+. (0.65 µM)
-
- A mixture of 4-methyl-5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one hydrochloride (62 mg, 0.21 mmol), (1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (40 mg, 0.21 mmol), and sodium triacetoxyborohydride (67 mg, 0.32 mmol) in DCM (5 mL) was stirred overnight with a drop of acetic acid. LC showed formation of the desired product, which was purified by mass-directed HPLC (0.1% TFA in water and acetonitrile). LC-MS (IE, m/z): 435 [M+1]+. (0.076 µM)
-
- To a solution of 4-bromo-2-fluorobenzonitrile (5.0 g, 13 mmol) in 100 ml of toluene was added LiCl (1.7 g, 39 mmol), Pd(PPh3)4 (400 mg), Allyl tributyltin (5.2 g, 16 mmol), and then the mixture was heated to reflux overnight. After the reaction was completed, the reaction solution was diluted with EtOAc and filtered. The filtrate was concentrated and purified with silica gel column chromatograph to give crude 4-allyl-2-fluorobenzonitrile.
- A solution of 4-allyl-2-fluorobenzonitrile (1 g, 6.2 mmol) in 1:1 CH2Cl2/MeOH (40 mL) containing pyridine (1 mL, 12.4 mmol) was cooled to -78 °C, and O3 was passed through until a blue color was present. N2 was then bubbled through to discharge the blue color and Me2S (5 ml) was added. The reaction mixture was allowed to warm and left overnight. The mixtue was washed with 1 N HCl and aqueous NaHCO3 and then dried and concentrated to give crude 2-fluoro-4-(2-oxoethyl)benzonitrile. The material was carried on as the crude.
- To a solution of crude 2-fluoro-4-(2-oxoethyl)benzonitrile (900 mg, 5.5 mmol) in 20 mL of DCM was added N-Boc Piperazine (1.0 g, 5.5 mmol) and NaBH(OAc)3 (4.7 g, 22 mmol), the mixture was stirred at room temperature overnight. The reaction was diluted with DCM, and washed with brine, the organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative TLC to give tert-butyl 4-[2-(4-cyano-3-fluorophenyl)ethyl]piperazine-1-carboxylate.
- To a solution of tert-butyl 4-[2-(4-cyano-3-fluorophenyl)ethyl]piperazine-1-carboxylate (440 mg, 1.32 mmol) in 10 mL of DMF was dropped NaSMe (0.66 mL, 1.8 mmol, 21 % in water). The mixture was stirred at 70 °C for 3 hours. The reaction was diluted with 40 mL of EtOAc and 40 mL water. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified with prep-TLC to give tert-butyl 4-{2-[4-cyano-3-(methylthio)phenyl]ethyl}piperazine-1-carboxylate (250 mg, 52 % yield). MS: m/e 362 (M+1)+. To a solution of tert-butyl4-{2-[4-cyano-3-(methylthio)phenyl]ethyl}piperazine-1-carboxylate (250 mg, 0.69 mmol) in 5 mL of DCM was added 5 mL of TFA was stirred at room temperature for 1 hours, and the reaction was concentrated. The residue was diluted with 30 mL of aq. NaHCO3 and 30 mL of DCM: MeOH (v/v=10/1). The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated to afford 2-(methylthio)-4-(2-piperazin-1-ylethyl)benzonitrile.
- To a solution of 2-(methylthio)-4-(2-piperazin-1-ylethyl)benzonitrile (0.69 mmol) in 20 mL of DCM was added (1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (180 mg, 1.03 mmol) and NaBH(OAc)3 (580 mg, 2.8 mmol), and the mixture was stirred at room temperature overnight. The reaction was diluted with DCM, and washed with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-TLC to give 2-(methylthio)-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile. 1H-NMR (400 MHz, CDC13) δ ppm 7.82 (d, J=8.6 Hz, 1H), 7.49 (d, J=7.8 Hz, 1H), 7.33∼7.37 (m, 2H), 7.16 (s, 1H), 7.02∼7.05 (m, 1H), 5.27 (s, 2H), 2.49∼3.01 (m, 19H). (0.55 µM)
-
- To a mixture of 5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one (90 mg, 0.190 mmol) and NaBH3CN (24 mg, 0.380 mmol) in 20 mL DCM was added 5-chloro-2-methoxy-4-(2-oxoethyl)benzonitrile (40 mg, 0.190 mmol) and the mixture was stirred at RT overnight. Concentrated, and the residue was purified by prep-TLC to give 5-chloro-2-methoxy-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile. 1H-NMR (400 MHz, MeOD) δ ppm 7.82 (d, J=7.8 Hz, 1H), 7.67 (s, 1H), 7.50∼7.53 (m, 2H), 7.20 (s, 1H), 5.35 (s, 2H), 3.95 (s, 3H), 3.23∼3.26 (m, 6H), 3.14∼3.16 (m, 8H), 3.00~3.03 (m, 2H). MS m/e 441 (M+1)+. (0.094 µM)
-
- To a solution of tert-butyl 4-[2-(4-cyano-3-fluorophenyl)ethyl]piperazine-1-carboxylate (100 mg, 0.30 mmol) in CH3CN (10 mL) was added aqueous NH2CH3 (10 mL) in a sealed tube, and then heated to 120 °C overnight. The mixture was extracted with EtOAc, washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified via prep-TLC to afford tert-butyl 4- {2- [4-cyano-3-(methylamino)phenyl]ethyl} piperazine-1 -carboxylate.
- A solution of tert-butyl 4-{2-[4-cyano-3-(methylamino)phenyl]ethyl}piperazine-1-carboxylate (18 mg, 0.05 mmol) in 5 mL of DCM was added TFA (3 mL), and then sirred at room temperature for 2 hours. The solvents were removed off under vacuum to afford crude 2-(methylamino)-4-(2-piperazin-1-ylethyl)benzonitrile.
- A solution of crude 2-(methylamino}-4-(2-piperazin-1-ylethyl)benzonitrile (∼18 mg, 0.05 mmol), (1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (9 mg, 0.05 mmol) and NaBH(OAc)3 (100 mg, 0.47 mmol) in 10 mL of anhydrous DCM was stirred at ambient temperature overnight. The reaction mixture was added 50 mL of DCM and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified with prep-TLC to afford 2-(methylamino)-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile. 1H-NMR (400 MHz, CDCl3) δ 7.77 (d, J=7.8,1H), 7.22∼7.32 (m, 3H), 6.42∼6.47 (m, 2H), 5.22 (s, 2H), 4.50∼4.58 (m, 1H), 2.84∼2.91 (m, 7H), 2.72∼2.77 (m, 2H), 2.53∼2.67 (m, 10H). (0.43 µM)
-
- To a stirred solution of 4-bromo-2-fluorobenzonitrile (4.0 g, 20 mmol) in DMF (20 mL) was added 2-(methylsulfonyl)ethanol (3.7 g, 30 mmol) and then NaH (2.4 g, 60 % in mineral, 60 mmol) in portions at 0 °C. The mixture was then warmed to rt. and quenched with 1N HCl, and extracted by EtOAc. The organic layers were washed with brine and dried over sodium sulfate, concentrated to give 4-bromo-2-hydroxybenzonitrile. 1H-NMR (400 MHz, DMSO) δ 7.55-7.57 (d, J = 8.61 Hz, 1H), 7.16 (s, 1H), 7.11-7.13 (m, 1H).
- A mixture of 4-bromo-2-hydroxybenzonitrile (2.0 g, 10 mmol), potassium carbonate (1.66g, 12 mmol), and ClF2CCOONa (3.0 g, 20 mmol) in DMF (18 mL) and H2O (2 mL) was degassed and kept at 100 °C for 2h. The resulting mixture was cooled to RT and then added concentrated HCl (3 mL) and H2O (4 mL) and then stirred at the temperature overnight. Then the mixture was brought to pH = 10.5 by addition of NaOH, and partitioned between water and MTBE. The organic layers were washed by water, saturated K3PO4 solution and brine, dried over sodium sulfate and concentrated to give 4-bromo-2-(difluoromethoxy)benzonitrile. 1H-NMR (400 MHz, CDCl3) δ 7.49-7.53 (m, 2H), 7.44-7.47 (m, 1H), 6.47-6.82 (t, J = 71.2 Hz, J = 71.2 Hz, 1H).
- To a solution of 4-bromo-2-(difluoromethoxy)benzonitrile (620 mg, 2.5 mmol) in 30 ml of toluene was added LiCl (322 mg, 7.5 mmol), Pd(PPh3)4 (60 mg), Allyl tributyltin (990 mg, 3.0 mmol), and then the mixture was heated to reflux overnight. After the reaction was completed, the reaction solution was diluted with EtOAc and filtered. The filtrate was concentrated and purified with silica gel column chromatograph to give crude 4-allyl-2-(difluoromethoxy) benzonitrile.
- A solution of 4-allyl-2-(difluoromethoxy)benzonitrile (600 mg, 2.9 mmol) in 1:1 CH2Cl2/MeOH (15 mL) containing pyridine (0.5 mL, 6 mmol) was cooled to -78 °C, and O3 was passed through until a blue color was present. N2 was then bubbled through to discharge the blue color and Me2S (5 ml) was added. The reaction mixture was allowed to warm and left overnight. The mixtue was washed with 1 N HCl, aqueous NaHCO3, dried and concentrated to give crude 2-(difluoromethoxy)-4-(2-oxoethyl)benzonitrile.
- A solution of crude compound 2-(difluoromethoxy)-4-(2-oxoethyl)benzonitrile (100 mg, 0.48 mmol), N-Boc Piperazine (100 mg, 0.54 mmol) and NaBH(OAc)3 (0.4 g, 2 mmol) in 20 mL of anhydrous DCM was stirred at ambient temperature overnight. The reaction mixture was added 50 mL of DCM, washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified with prep-TLC to afford tert-butyl-4-{2-[4-cyano-3-(difluoromethoxy)phenyl]ethyl}piperazine-1-carboxylate (50 mg, 27% yield). The material was further treated with TFA to remove the Boc group. The crude product was used directly in the next step. MS: m/e 282 (M+1)+.
- A solution of crude 2-(difluoromethoxy)-4-(2-piperazin-1-ylethyl)benzonitrile (15 mg, 0.05 mmol), (1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (18 mg, 0.1 mmol) and NaBH(OAc)3 (100 mg, 0.47 mmol) in 10 mL of anhydrous DCM was stirred at ambient temperature overnight. The reaction mixture was added 50 mL of DCM, washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified with prep-TLC to afford 2-(difluoromethoxy)-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile. 1H-NMR (400 MHz, CDCl3) δ 7.82 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 8.6 Hz, 1H), 7.33∼7.36 (m, 2H), 7.13∼7.20 (m, 2H), 6.33 (t, J = 71.2 Hz, 1H), 5.26 (s, 2H), 2.99∼3.08 (m, 2H), 2.87∼2.90 (m, 2H), 2.62∼2.84 (m, 12H). (0.15 µM)
-
- A mixture of 4-bromo-2-hydroxybenzonitrile (300 mg, 1.5 mmol), bromo-cyclopropane (480 mg, 4.0 mmol) and Cs2CO3 (300 mg, 1.6 mmol) in 2 mL of anhydrous DMF were heated to 170 °C for 2 hours by microwave. The solid was filtered off, and the filtrate was poured to water, and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified with prep-TLC to give 4-bromo-2-(cyclopropyloxy) benzonitrile. 1H-NMR (400 MHz, CDCl3) δ ppm 7.46~7.48 (m, 1H), 7.36∼7.38 (m, 1H), 7.14∼7.16 (m, 1H), 3.79∼3.84 (m, 1H), 0.86~0.87 (m, 4H).
- To a solution of 4-bromo-2-(cyclopropyloxy)benzonitrile (108 mg, 0.45 mmol) in 20 ml of toluene was added LiCl (38 mg, 0.9 mmol), Pd(PPh3)4 (15 mg), allyl tributyltin (180 g, 0.55 mmol), then the mixture was heated to reflux overnight. After the reaction was completed, the reaction solution was diluted with EtOAc and filtered, the filtrate was concentrated and purified with silica gel column chromatograph to give crude 4-allyl-2-(cyclopropyloxy)benzonitrile.
- A solution of 4-allyl-2-(cyclopropyloxy)benzonitrile (100 mg, 0.5 mmol) in 1:1 CH2Cl2/MeOH (15 mL) containing pyridine (0.5 mL, 6 mmol) was cooled to -78 °C, and O3 was passed through until a blue color was present. N2 was then bubbled through to discharge the blue color and Me2S (5 ml) was added. The reaction mixture was allowed to warm and left overnight. The mixtue was washed with 1 N HCl and aqueous NaHCO3 and then dried and concentrated to give crude 2-(cyclopropyloxy)-4-(2-oxoethyl)benzonitrile.
- A solution of crude 2-(cyclopropyloxy)-4-(2-oxoethyl)benzonitrile (80 mg, 0.4 mmol), 5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one (150 mg, 0.6 mmol) and NaBH(OAc)3 (400 mg, 2 mmol) in 10 mL of anhydrous DCM was stirred at ambient temperature overnight. The reaction mixture was added 50 mL of DCM and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified with prep-TLC to afford 2-(cyclopropyloxy)-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile. 1H-NMR (400 MHz, CDCl3) δ ppm 7.77 (d, J=7.8 Hz, 1H), 7.37 (d, J=7.8 Hz, 1H), 7.31 (d, J=7.8 Hz, 1H), 7.27 (s, 1H), 7.11 (s, 1H), 6.78~6.80 (m, 1H), 5.22 (s, 2H), 2.42∼2.93 (m, 17H), 0.77∼0.80 (m, 4H). (0.28 µM)
-
- A 4-neck, 22-L, round bottom flask equipped with a mechanical stirrer, thermocouple, nitrogen bubbler, and condenser was charged with 5-bromophthalide (650 g, 3.0 mol), allyltri-n-butyhin (1200 g, 3.6 mol), tetrakis(triphenylphosphine)palladium (100 g, 0.089 mol), lithium chloride (250 g, 5.9 mol) and toluene (8.8 L). The mixture was evacuated and flushed with nitrogen 3 times and then was stirred at 100 °C for 4 hours. After slowly cooling to ambient temperature, the mixture was filtered and concentrated. The resulting solid was purified by silica gel column chromatography (heptane:ethyl acetate, 0→40%) to provide 5-allyl-2-benzofuran-1(3H)-one. 1H NMR (500 MHz, CD3OD) δ 7.83 (d, J= 8.0 Hz, 1H), 7.38 (d, J= 8.0 Hz, 1H), 7.33 (s, 1H), 5.98 (m, 1H), 5.29 (s, 2H), 5.11-5.18 (m, 2H), 3.52 (d, J = 8.2 Hz, 2H); LC-MS (IE, m/z): 175.1 [M + 1]+.
- Ozone was bubbled through a solution of 5-allyl-2-benzofuran-1(3H)-one (125 mg, 0.72 mmol) in DCM until the color changed to orange. Removed excess ozone by bubbling nitrogen through solution for a minute. Added a solution of 1-[2-(4-nitrophenyl)ethyl]piperazine hydrochloride (65 mg, 0.24 mmol) and triethylamine (0.033 mL, 0.24 mmol) in DCM (2 mL), followed by NaB(OAc)3H (250 mg, 1.2 mmol). The mixture was allowed to stir at RT for 16 hours. HPLC-MS shows product but reaction is not clean. The product was urified by prep-TLC to afford 5-(2-{4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl}ethyl)-2-benzofuran-1(3H)-one as a white solid. LC-MS (IE, m/z): 396 [M + 1]+. (0.089 µM)
-
-
- A mixture of 5-(2-bromoethyl)-2-benzofuran-1(3H)-one (130 mg, 0.54 mmol) and 5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one hydrochloride (76 mg, 0.27 mmol) was heated to 60 °C with triethylamine (0,19 mL, 1.3 mmol) and DMF (2 mL) for 24 hours. LC showed formation of the desired product. The crude reaction was diluted with EtOAc, washed with water, dried over magnesium sulfate, and purified by prep-TLC. About 26 mg pure product was collected after removal of solvent. LC-MS (IE, m/z): 407 [M + 1]+. (0.089 µM)
-
- 2-Trifluoromethoxy-4-(2-oxoethyl)benzonitrile (67 mg, 0.30 mmol) was taken up in 1,2-dichloromethane (DCE) (2 mL) and 5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride (85 mg, 0.30 mmol) and DIPEA (0.104 mL, 0.60 mmol) were added. After stirring the mixture for 15 minutes at room temperature, sodium triacetoxyborohydride (102 mg, 0.48 mmol) was added. After 16 hours, LC-MS indicated product formation and most of the volatiles were evaporated under a stream of nitrogen. The residue was taken up in acetonitrile/water (total 3 mL) and acidified with TFA. The product was isolated by reverse phase HPLC (eluted with a gradient of 10-50% acetonitrile/water (0.1% TFA) over 24 minutes). The clean main fractions by LC-MS were evaporated to give the TFA salt which was converted to the di-HCl salt of the title compound. LC-MS (IE, m/z): 460 [M + 1 ]+. (0.62 µM)
-
- 2-Trifluoromethoxy-4-(2-oxoethyl)benzonitrile (67 mg, 0.30 mmol) was taken up in DCE (2 mL) and 4-methyl-5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride (88 mg, 0.30 mmol) and DIPEA (0.100 mL, 0.60 mmol) were added. After stirring the mixture for 15 minutes at room temperature, sodium triacetoxyborohydride (102 mg, 0.48 mmol) was added. After 16 hours, LC-MS indicated product formation and most of the volatiles were evaporated under a stream of nitrogen. The residue was taken up in acetonitrile/water (total 3 mL) and acidified with TFA. The product was isolated by reverse phase HPLC (eluted with a gradient of 10-50% acetonitrile/water (0.1% TFA) over 24 minutes). The clean main fractions by LC-MS were evaporated to give the TFA salt which was converted to the di-HCl salt of the title compound. LC-MS (IE, m/z): 474 [M+ 1]+. (0.20 µM)
-
- 2-Chloro-4-(2-oxoethyl)benzonitrile (79 mg, 0.44 mmol) was taken up in DCE (2 mL) and 5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride (124 mg, 0.44 mmol) and DIPEA (0.150 mL, 0.88 mmol) were added. After stirring the mixture for 15 minutes at room temperature, sodium triacetoxyborohydride (149 mg, 0.70 mmol) was added. After 16 hours, LC-MS indicated product formation and most of the volatiles were evaporated under a stream of nitrogen. The residue was taken up in acetonitrile/water (total 3 mL) and acidified with TFA. The product was isolated by reverse phase HPLC (eluted with a gradient of 10-50% acetonitrile/water (0.1 % TFA) over 24 minutes). The clean main fractions by LC-MS were evaporated to give the TFA salt which was converted to the di-HCl salt of the title compound. LC-MS (IE, m/z): 410/412 [M + 1]+. (0.075 µM)
-
- 2-Chloro-4-(2-oxoethyl)benzonitrile (79 mg, 0.44 mmol) was taken up in DCE (2 mL) and 4-methyl-5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride (131 mg, 0.44 mmol) and DIPEA (0.150 mL, 0.88 mmol) were added. After stirring the mixture for 5 minutes at room temperature, sodium triacetoxyborohydride (149 mg, 0.70 mmol) was added. After 16 hours, LC-MS indicated product formation and most of the volatiles were evaporated under a stream of nitrogen. The residue was taken up in acetonitrile/water (total 3 mL) and acidified with TFA. The product was isolated by reverse phase HPLC (eluted with a gradient of 10-50% acetonitrile/water (0.1 % TFA) over 24 minutes). The main clean fractions by LC-MS were evaporated to give the TFA salt which was converted to the di-HCl salt of the title compound. LC-MS (IE, m/z): 424/426 [M + 1]+. (0.035 µM)
-
- 3-Fluoro-2-methoxy-4-(2-oxoethyl)benzonitrile (15 mg, 0.15 mmol) was taken up in (DCE) (2 mL) and 5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride (43 mg, 0.15 mmol) and DIPEA (0.55 mL, 0.31 mmol) were added. After stirring the mixture for 15 minutes at room temperature, sodium triacetoxyborohydride (52 mg, 0.25 mmol) was added. After 16 hours, LC-MS indicated product formation and most of the volatiles were evaporated under a stream of nitrogen. The residue was taken up in acetonitrile/water (total 3 mL) and acidified with TFA. The product was isolated by reverse phase HPLC (eluted with a gradient of 10-50% acetonitrile/water (0.1% TFA) over 24 minutes). The clean main fractions by LC-MS were evaporated to give the TFA salt which was converted to the di-HCl salt of the title compound. LC-MS (IE, m/z): 424 [M + 1]+. (0.092 µM)
-
- 3-Fluoro-2-methoxy-4-(2-oxoethyl)benzonitrile (30 mg, 0.15 mmol) was taken up in DCE (2 mL) and 4-methyl-5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride (45 mg, 0.15 mmol) and DIPEA (0.55 mL, 0.31 mmol) were added. After stirring the mixture for 15 minutes at room temperature, sodium triacetoxyborohydride (52 mg, 0.25 mmol) was added. After 16 hours, LC-MS indicated product formation and most of the volatiles were evaporated under a stream of nitrogen. The residue was taken up in acetonitrile/water (total 3 mL) and acidified with TFA. The product was isolated by mass directed LC-MS (eluted with a gradient of 10-50% acetonitrile/water (0.05% TFA)). The main fractions containing M+1 = 438) were evaporated to give the TFA salt which was converted to the di-HCl salt of the title compound. LC-MS (IE, m/z): 438 [M + 1]+. (0.091 µM)
-
- 4-(2-Oxoethyl)naphthalene-1-carbonitrile (21 mg, 0.11 mmol) was taken up in methanol (2 mL) and 4-methyl-5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride (33 mg, 0.11 mmol) was added (no DIPEA). After stirring the mixture for 15 minutes at room temperature, sodium cyanoborohydride (14 mg, 0.22 mmol) was added. After 16 hours, LC-MS indicated product formation and most of the volatiles were evaporated under a stream of nitrogen. The residue was taken up in acetonitrile/water (total 3 mL) and acidified with TFA. The product was isolated by mass directed LC-MS (eluted with a gradient of 10-50% acetonitrile/water (0.05% TFA)). The main fractions containing M+1 = 440) were evaporated to give the TFA salt which was converted to the di-HCl salt of the title compound. LC-MS (IE, m/z): 440 [M + 1]+. (0.16 µM)
-
- 4-(2-Oxoethyl)-2,3,5-trifluoro-benzonitrile (22 mg, 0.11 mmol) was taken up in methanol (2 mL) and 4-methyl-5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride (32 mg, 0.11 mmol) was added (no DIPEA). After stirring the mixture for 10 minutes at room temperature, sodium cyanoborohydride (14 mg, 0.22 mmol) was added. After 16 hours, LC-MS indicated product formation and most of the volatiles were evaporated under a stream of nitrogen. The residue was partitioned with DCM (2x) /aqueous sodium carbonate and the organic layers were washed with brine, dried over sodium sulfate and evaporated. The residue was taken up in acetonitrile/water (total 3 mL) and acidified with TFA. The product was isolated by mass directed LC-MS (eluted with a gradient of 10-50% acetonitrile/water (0.05% TFA)). The main fractions containing M+1 = 444) were evaporated to give the TFA salt which was converted to the di-HCl salt of the title compound. LC-MS (IE, m/z): 444 [M + 1]+. (0.23 µM)
-
- 2-Ethoxy-4-(2-oxoethyl)benzonitrile (26 mg, 0.14 mmol) was taken up in methanol (2 mL) and 5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride (40 mg, 0.14 mmol) (no DIPEA) was added. After stirring the mixture for 15 minutes at room temperature, sodium cyanoborohydride (18 mg, 0.28 mmol) was added. After 16 hours, LC-MS indicated product formation. Most of the methanol was evaporated under a stream of nitrogen and the residue was diluted with aqueous sodium carbonate and extracted 2x with DCM. The organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was taken up in acetonitrile/water (total 4 mL) and acidified with TFA and the product was isolated by mass directed LC-MS (eluted with a gradient of 10-50% acetonitrile/water (0.05% TFA)). The main fractions containing M+1 = 420) were evaporated to give the TFA salt which was converted to the di-HCl salt of the title compound. LC-MS (IE, m/z): 420 [M + 1]+. 1H-NMR (500 MHz, CD3CN) δ ppm 1.335 (t, J= 7.0 Hz, 3H), 3.05 (m, 2H), 3.11 (m, 2H), 3.25 (m, 4H), 3.48 (br s, 8H), 4.10 (q, J = 7.0 Hz, 2H), 4.0 (v br s, 2 +NH), 5.214 (s, 2H), 6.854 (d, J = 7.9 Hz, 1H), 6.947 (s, 1H), 7.375 (d, J = 8.1 Hz, 1H), 7.397 (s, 1H), 7.473 (d, J = 8.0 Hz, 1H),. 7.719 (d, J= 7.8 Hz, 1H). (0.053 µM)
-
- 2-Ethoxy-4-(2-oxoethyl)benzonitrile (27 mg, 0.14 mmol) was taken up in methanol (2 mL) and 4-methyl-5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride (42 mg, 0.14 mmol) (no DIPEA) was added. After stirring the mixture for 15 minutes at room temperature, sodium cyanoborohydride (18 mg, 0.28 mmol) was added. After 16 hours, LC-MS indicated product formation and most of the methanol was evaporated under a stream of nitrogen. The residue was diluted with aqueous sodium carbonate and extracted 2x with DCM. The organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was taken up in acetonitrile/water (total 3 mL) and acidified with TFA and the product was isolated by mass directed LC-MS (2 runs, eluted with a gradient of 10-50% acetonitrile/water (0.05% TFA)). The clean main fractions containing M+1 = 434) were evaporated to give the TFA salt which was converted to the di-HCl salt of the title compound. LC-MS (IE, m/z): 434 [M + 1]+. (0.074 µM)
-
- 5-Chloro-2-fluoro-4-(2-oxoethyl)benzonitrile (28 mg, 0.14 mmol) was taken up in methanol (2 mL) and 5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride (40 mg, 0.14 mmol) and DIPEA (0.025 mL, 0.14 mmol) were added. After stirring the mixture for 5 minutes at room temperature, sodium cyanoborohydride (18 mg, 0.28 mmol) was added. After 16 hours, LC-MS indicated product formation. Most of the methanol was evaporated under a stream of nitrogen and the residue was diluted with aqueous sodium carbonate and extracted 2x with DCM. The organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was taken up in acetonitrile/water (total 3 mL) and acidified with TFA and the product was isolated by mass directed LC-MS (eluted with a gradient of 10-50% acetonitrile/water (0.05% TFA)). The main fractions containing M+1 = 428) were evaporated to give the TFA salt which was converted to the di-HCl salt of the title compound. LC-MS (IE, m/z): 428/430 [M + 1]+. (0.076 µM)
-
- 5-Chloro-2-fluoro-4-(2-oxoethyl)benzonitrile (55 mg, 0.28 mmol) was taken up in methanol (2 mL) and 4-methyl-5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride (83 mg, 0.28 mmol) and DIPEA (0.050 mL, 0.28 mmol) were added. After stirring the mixture for 5 minutes at room temperature, sodium cyanoborohydride (35 mg, 0.56 mmol) was added. After 16 hours, LC-MS indicated product formation. Most of the methanol was evaporated under a stream of nitrogen. The residue was diluted with aqueous sodium carbonate and extracted 2x with DCM. The organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was taken up in acetonitrile/water (total 4 mL) and acidified with TFA and the product was isolated by mass directed LC-MS (eluted with a gradient of 10-50% acetonitrile/water (0.05% TFA)). The clean main fractions containing M+1 = 442) were evaporated to give the TFA salt which was converted to the di-HCl salt of the title compound. LC-MS (IE, m/z): 442/444 [M + 1]+. 1H-NMR (500 MHz, CD3CN) δ ppm 2.210 (s, 3H), 2.7 (v br s, 2 +NH), 2.93 (m, 2H), 3.05 (m, 2H), 3.09 (br s, 8H), 3.12 (br s, 2H), 3.30 br s, 2H) 5.199 (s, 2H), 7.316 (d, J = 9.1 Hz, 1H), 7.328 (d, J= 7.2 Hz, 1H), 7.563 (d, J= 7.8 Hz, 1H),. 7.738 (d, J = 5.9 Hz, 1H). (0.048 µM)
-
- 5-Chloro-2-methoxy-4-(2-oxoethyl)benzonitrile (46 mg, 0.22 mmol) was taken up in methanol (2 mL) and 4-methyl-5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride (65 mg, 0.22 mmol) and DIPEA (0.040 mL, 0.22 mmol) were added. After stirring the mixture for 5 minutes at room temperature, sodium cyanoborohydride (28 mg, 0.44 mmol) was added. After 16 hours, LC-MS indicated product formation. Most of the methanol was evaporated under a stream of nitrogen. The residue was diluted with aqueous sodium carbonate and extracted 2x with DCM. The organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was taken up in acetonitrile/water (total 3 mL) and acidified with TFA and the product was isolated by mass directed LC-MS (eluted with a gradient of 10-50% acetonitrile/water (0.05% TFA)). The clean main fractions containing M+1 = 454/456) were evaporated to give the TFA salt which was converted to the di-HCl salt of the title compound. LC-MS (IE, m/z): 454/456 [M + 1]+. (0.071 µM)
-
- 2-Fluoro-3-methyl-4-(2-oxoethyl)benzonitrile (21 mg, 0.12 mmol) was taken up in methanol (2 mL) and 5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride (34 mg, 0.12 mmol) and DIPEA (0.020 mL, 0.12 mmol) were added. After stirring the mixture for 5 minutes at room temperature, sodium cyanoborohydride (15 mg, 0.24 mmol) was added. After 16 hours, LC-MS indicated product formation. Most of the methanol was evaporated under a stream of nitrogen and the residue was diluted with aqueous sodium carbonate and extracted 2x with DCM. The organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was taken up in acetonitrile/water (total 3 mL) and acidified with TFA and the product was isolated by mass directed LC-MS (eluted with a gradient of 10-50% acetonitrile/water (0.05% TFA)). The main fractions containing M+1 = 408) were evaporated to give the TFA salt which was converted to the di-HCl salt of the title compound.
LC-MS (IE, m/z): 408 [M + 1]+. 1H-NMR (500 MHz, CD3CN) δ ppm 2.25 (s, 3H), 2.6-3.6 (v br s, 2 +NH), 3.05, 3.15, 3.31 (br s, m, br s, 16H), 5.284 (s, 2H), 7.196 (d, J= 8.0 Hz, 1H), 7.460 (d,J= 7.8 Hz, 1H), 7.467 (s, 1H), 7.53 (t, J = 8.0 Hz, 1H),. 7.778 (d, J = 7.8 Hz, 1H). (0.080 µM) -
- 2-Fluoro-3-methyl-4-(2-oxoethyl)benzonitrile (42 mg, 0.24 mmol) was taken up in methanol (4 mL) and 4-methyl-5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride (71 mg, 0.24 mmol) and DIPEA (0.0420 mL, 0.24 mmol) were added. After stirring the mixture for 5 minutes at room temperature, sodium cyanoborohydride (30 mg, 0.48 mmol) was added. After 16 hours, LC-MS indicated product formation. Most of the methanol was evaporated under a stream of nitrogen. The residue was diluted with aqueous sodium carbonate and extracted 2x with DCM. The organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was taken up in acetonitrile/water (total 3 mL) and acidified with TFA and the product was isolated by mass directed LC-MS (eluted with a gradient of 10-50% acetonitrile/water (0.05% TFA)). The clean main fractions containing M+1 = 422) were evaporated to give the TFA salt which was converted to the di-HCl salt of the title compound. LC-MS (IE, m/z): 422 [M + 1]+. (0.063 µM)
-
- 2-Methoxy-3-methyl-4-(2-oxoethyl)benzonitrile (20 mg, 0.106 mmol) was taken up in methanol (2 mL) and 5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride (32.5 mg, 0.13 mmol) and DIPEA (0.032 mL, 0.18 mmol) were added. After stirring the mixture for 5 minutes at room temperature, sodium cyanoborohydride (13.2 mg, 0.21 mmol) was added. After 1 hour, LC-MS indicated product formation. Most of the methanol was evaporated under a stream of nitrogen and the residue was diluted with aqueous sodium carbonate and extracted 3x with DCM. The organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was taken up in acetonitrile/water (total 4 mL) and acidified with TFA and the product was isolated by mass directed LC-MS (eluted with a gradient of 10-50% acetonitrile/water (0.05% TFA)). The main fractions containing M+1 = 420) were evaporated to give the TFA salt which was converted to the di-HCl salt of the title compound. LC-MS (IE, m/z): 420 [M + 1]+. (0.18 µM)
-
- 2-Methoxy-3-methyl-4-(2-oxoethyl)benzonitrile (40 mg, 0.21 mmol) was taken up in methanol (4 mL) and 4-methyl-5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride (32.5 mg, 0.132 mmol) and DIPEA (0.065 mL, 0.37 mmol) were added. After stirring the mixture for 5 minutes at room temperature, sodium cyanoborohydride (26.4 mg, 0.42 mmol) was added. After 1 hour, LC-MS indicated product formation. Most of the methanol was evaporated under a stream of nitrogen. The residue was diluted with aqueous sodium carbonate and extracted 3x with DCM. The organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was taken up in acetonitrile/water (total 7 mL) and acidified with TFA and the product was isolated by mass directed LC-MS (2 runs, eluted with a gradient of 10-50% acetonitrile/water (0.05% TFA)). The main fractions containing M+1 = 434) were evaporated to give the TFA salt which was converted to the di-HCl salt of the title compound. LC-MS (IE, m/z): 434 [M + 1]+. (0.078 µM)
-
- 3-Chloro-2-fluoro-4-(2-oxoethyl)benzonitrile (20 mg, 0.10 mmol) was taken up in methanol (3 mL) and 5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one (20 mg free base, 0.080 mmol) was added (no DIPEA since piperidine free amine was used). After stirring the mixture for 15 minutes at room temperature, sodium cyanoborohydride (10 mg, 0.15 mmol) was added. After 16 hours, LC-MS indicated product formation. Most of the methanol was evaporated under a stream of nitrogen and the residue was diluted with aqueous sodium carbonate and extracted 2x with DCM. The organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was taken up in acetonitrile/water (total 4 mL) and acidified with TFA and the product was isolated by mass directed LC-MS (eluted with a gradient of 10-50% acetonitrile/water (0.05% TFA)). The main fractions containing M+1 = 428) were evaporated to give the TFA salt which was converted to the di-HCl salt of the title compound. LC-MS (IE, m/z): 428/430 [M + 1]+. (0.13 µM)
-
- 3-Chloro-2-fluoro-4-(2-oxoethyl)benzonitrile (42 mg, 0.21 mmol) was taken up in methanol (3 mL) and 4-methyl-5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one (44 mg, 0.28 mmol free base) was added (no DIPEA since piperidine free amine was used). After stirring the mixture for 5 minutes at room temperature, sodium cyanoborohydride (20 mg, 0.315 mmol) was added. After 16 hours, LC-MS indicated product formation. Most of the methanol was evaporated under a stream of nitrogen. The residue was diluted with aqueous sodium carbonate and extracted 2x with DCM. The organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was taken up in acetonitrile/water (total 3 mL) and acidified with TFA and the product was isolated by mass directed LC-MS (eluted with a gradient of 10-50% acetonitrile/water (0.05% TFA)). The clean main fractions containing M+1 = 442) were evaporated to give the TFA salt which was converted to the di-HCl salt of the title compound. LC-MS (IE, m/z): 442/444 [M + 1]+. (0.078 µM)
-
- 3-Chloro-2-methoxy-4-(2-oxoethyl)benzonitrile (26 mg, 0.125 mmol) was taken up in methanol (2 mL) and 5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride (28 mg, 0.100 mmol) and DIPEA (0.017 mL, 0.100 mmol) were added. After stirring the mixture for 5 minutes at room temperature, sodium cyanoborohydride (10 mg, 0.150 mmol) was added. After 16 hours, LC-MS indicated product formation. Most of the methanol was evaporated under a stream of nitrogen and the residue was diluted with aqueous sodium carbonate and extracted 2x with DCM. The organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was taken up in acetonitrile/water (total 3 mL) and acidified with TFA and the product was isolated by mass directed LC-MS (eluted with a gradient of 10-50% acetonitrile/water (0.05% TFA)). The main fractions containing M+1 = 440) were evaporated to give the TFA salt which was converted to the di-HCl salt of the title compound. LC-MS (IE, m/z): 440/442 [M + 1]+. (0.16 µM)
-
- 3-Chloro-2-methoxy-4-(2-oxoethyl)benzonitrile (52 mg, 0.25 mmol) was taken up in methanol (2 mL) and 4-methyl-5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride (67 mg, 0.20 mmol) and DIPEA (0.035 mL, 0.20 mmol) were added. After stirring the mixture for 5 minutes at room temperature, sodium cyanoborohydride (25 mg, 0.40 mmol) was added. After 16 hours, LC-MS indicated product formation. Most of the methanol was evaporated under a stream of nitrogen. The residue was diluted with aqueous sodium carbonate and extracted 2x with DCM. The organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was taken up in acetonitrile/water (total 3 mL) and acidified with TFA and the product was isolated by mass directed LC-MS (eluted with a gradient of 10-50% acetonitrile/water (0.05% TFA)). The clean main fractions containing M+1 = 454) were evaporated to give the TFA salt which was converted to the di-HCl salt of the title compound. LC-MS (IE, m/z): 454/456 [M + 1]+. (0.083 µM)
-
- 4-Fluoro-2-methoxy-3-(2-oxoethyl)benzonitrile (35 mg, 0.18 mmol) was taken up in methanol (2 mL) and 5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride (41 mg, 0.14 mmol) was added (no DIPEA). After stirring the mixture for 5 minutes at room temperature, sodium cyanoborohydride (17 mg, 0.27 mmol) was added. After 16 hours, LC-MS indicated product formation. Most of the methanol was evaporated under a stream of nitrogen and the residue was diluted with aqueous sodium carbonate and extracted 2x with DCM. The organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was taken up in acetonitrile/water (total 3 mL) and acidified with TFA and the product was isolated by mass directed LC-MS (eluted with a gradient of 10-50% acetonitrile/water (0.05% TFA)). The main fractions containing M+1 = 424) were evaporated to give the TFA salt which was converted to the di-HCl salt of the title compound. LC-MS (IE, m/z): 424 [M + 1]+. (0.13 µM)
-
- 4-Fluoro-2-methoxy-3-(2-oxoethyl)benzonitrile (35 mg, 0.18 mmol) was taken up in methanol (2 mL) and 4-methyl-5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one hydrochloride (43 mg, 0.14 mmol) was added (no DIPEA). After stirring the mixture for 5 minutes at room temperature, sodium cyanoborohydride (17 mg, 0.27 mmol) was added. After 16 hours, LC-MS indicated product formation. Most of the methanol was evaporated under a stream of nitrogen. The residue was diluted with aqueous sodium carbonate and extracted 2x with DCM. The organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was taken up in acetonitrile/water (total 3 mL) and acidified with TFA and the product was isolated by mass directed LC-MS (eluted with a gradient of 10-50% acetonitrile/water (0.05% TFA)). The clean main fractions containing M+1 = 438) were evaporated to give the TFA salt which was converted to the di-HCl salt of the title compound LC-MS (IE, m/z): 438 [M + 1]+. (0.043 µM)
-
- To a solution of 4-formyl-3,4-dihydro-2H-chromene-7-carbonitrile (50 mg, 0.27 mmol) in DCM (3 mL) was added 4-methyl-5-[2-(piperazine-1-yl)ethyl]-2-benzofuran-1(3H)-one (57 mg, 0.27 mmol), sodium triacetoxyborohydride (27.0 mg, 0.267 mmol) and DIPEA (57 mg, 0.27 mmol). The reaction was stirred under nitrogen at room temperature for 16 hours when LC-MS indicated product formation. The mixture was diluted with DCM and the product was isolated by flash chromatography. LC-MS (IE, m/z): 432 [M + 1]+. (0.18 µM)
-
- To a 12 mL reaction vial was added 6-fluoro-4-formyl-3,4-dihydro-2H-chromene-7-carbonitrile (12 mg, 0.058 mmol), 5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one (14.4 mg, 0.058 mmol) and dichloromethane (3 mL). The solution was stirred at RT under N2 for 10 min. To above solution was added NaB(OAc)3H (49.6 mg, 0.23 mmol, 4.0 eq). The reaction was stirred at RT for 18 hours under N2, extracted with DCM, washed with brine and water. The organic phase was dried over MgSO4, filtered and purified by flash column chromatography. LC-MS (IE, m/z): 436.3 [M + 1]+. (0.44 µM)
-
- To a 12 mL reaction vial was added 2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)propanal (60 mg, 0.29 mmol), piperazine (12.7 mg, 0.15 mmol) and dichloromethane (5 mL). The solution was stirred at RT under N2 for 10 min. To above solution was added NaB(OAc)3H (125 mg, 0.59 mmol). The reaction was stirred at RT for 18 hours under N2, extracted with DCM, washed with brine and water. The organic phase was dried over MgSO4, filtered and purified by flash column chromatography to give desired product. LC-MS (IE, m/z): 463.4 [M + 1]+. 1H NMR (500 MHz, CDCl3, δ in ppm): 7.72 (2H, d, J = 8.0 Hz), 7.38 (2H, d, J = 8.0 Hz), 5.23 (4H, s), 3.29 (2H, q), 2.3 - 2.5 (10H, m), 2.27 (6H, s), 1.25 (6H, d, J= 6.8 Hz). (0.22 µM)
-
- To a 12 mL reaction vial was added 4-methyl-5-[1-(piperazine-1-yl)propan-2-yl]-2-benzofuran-1(3H)-one (57 mg, 0.208 mmol), (4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (47.4 mg, 0.25 mmol) and dichloromethane (5 mL). The solution was stirred at RT under N2 for 10 min. To above solution was added NaB(OAc)3H (88 mg, 0.42 mmol). The reaction was stirred at RT for 18 hours under N2, extracted with DCM, washed with brine and water. The organic phase was dried over MgSO4, filtered and purified by flash column chromatography to give desired product. LC-MS (IE, m/z): 449.4 [M + 1]+. 1H NMR (500 MHz, CDCl3, δ in ppm): 7.73 (1H, d, J = 8.0 Hz), 7.67 (1H, d, J = 8.0 Hz), 7.40 (1H, d, J = 8.0 Hz), 7.32 (1H, d, J = 8.0 Hz), 5.25 (2H, s), 5.23 (2H, s), 3.33 (1H, q), 2.90 (2H, m), 2.4 - 2.6 (12H, m), 2.30 (3H, s), 2.27 (3H, s), 1.28 (3H, d, J= 6.6 Hz). (0.034 µM)
-
- A mixture of 5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one (50 mg, 0.20 mmol), 4-(2-Oxoethyl)benzonitrile (30 mg, 0.20 mmol), Sodium Cyanoborohydride (13 mg, 0.20 mmol), and a drop of HOAc was stirred together in Methanol for 2 hours. LC showed formation of the desired product. The crude was diluted with EtOAc, washed with water, adsorbed onto silica gel, and purified by silica gel chromatography. LC-MS (IE, m/z): 376 [M + 1]+. (0.30 µM)
- Several assays may be used to measure functional inhibition of the ROMK channel by compounds of the instant invention. One primary assay that can be used is a functional 86Rb+ efflux assay that measures the ability of ROMK to permeate 86Rb+, in the absence or presence of test compound. Under control conditions, cells loaded with 86Rb+ and incubated in Rb+-free medium display a time-dependent efflux of the isotope, the rate of which depends on number of functional channels. When cells are incubated in the presence of a channel inhibitor, efflux of 86Rb+ is prevented in a concentration-dependent manner, and IC50 values of inhibition by compounds can be accurately determined. This assay has been established with cell lines expressing either human, rat or dog ROMK channels, and can operate in 96- or 384-well format. Importantly, the human, rat, and dog 86Rb+ efflux assays can be carried out in the presence of up to 100% serum allowing, therefore, an accurate estimation of the effect of protein binding on the inhibitory activity of compounds of interest. Another ROMK functional assay makes use of the ability of thallium to permeate through open ROMK channels and increase the fluorescence of a dye previously loaded into the cells. Under control conditions, cells loaded with dye and exposed to thallium-containing medium display a time-dependent increase in fluorescence, the rate of which depends on number of functional channels. When cells are incubated in the presence of a channel inhibitor, the increase in fluorescence is attenuated in a concentration-dependent manner, and IC50 values of inhibition by compounds can be accurately determined. This assay has been established with cell lines expressing either human, or rat ROMK channels, and operates in 384-well format.
- Cell Culture Conditions- CHO-DHFR- cells stably expressing hROMK1 (Kir1.1) are grown at 37°C in a 10%CO2 humidified incubator in Iscove's Modified Dulbecco's Medium (Gibco 12440) supplemented with HT Supplement, Penicillin/Streptomycin/Glutamine, G418 (500 µg/ml) and 10% FBS. Cells are seeded in Sterile and Tissue Culture Treated Packard CulturPlate White Opaque Microplates at a concentration of 5.0E5 - 7.0E5 cells/ml - PerkinElmer 6005680 (96-well); Corning 3707 (384 well) in complete media containing 1.5 µCi/ml Rubidium-86. Cells are incubated in 37°C-10% CO2 incubator overnight. On the day of the experiment, the media is removed and cells are washed with low K assay buffer. 86Rb+ efflux is initiated after addition of assay buffer ± test compound followed by 35 min incubation at room temperature. ROMK-sensitive component of efflux is defined in the presence of 10 mM BaCl2. Assay buffer is removed and transferred to a plate and cells are solubilized in the presence of SDS. Radioactivity associated with assay and cell plate is determined.
-
- 1. Remove cell media and wash cells with low K assay buffer (126.9 mM NaCl, 4.6 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 10 mM Hepes/NaOH; pH 7.4)
- 200 µl for 96-well plate; 70 µl for 384-well plate
- 2. Add assay buffer (121.5 mM NaCl, 10 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 10 mM Hepes/NaOH; pH 7.4) ± test compound to cells
- 100 µl for 96-well plate; 50 µl for 384-well plate
- 3. Incubate at ambient temperature (22-24°C) for 35 min
- 4. Remove assay buffer add it to a 96- or 384-well plate containing Microscint-20
- 96-well Plate: 100 µl buffer, 170 µl MicroScint 20 (for TopCount)
- 384-well plate: 20 µl buffer, 50 µl Optiphiase (for MicroLux)
- 5. Completely remove remaining assay buffer from cell plate
- 6. Solubilize cells with 1% SDS; than add MicroScint or Optiphase
- 96-well Plate: 30 µl SDS, 170 µl MicroScint 20 (for TopCount)
- 384-well plate: 20 µl SDS, 50 µl Optiphiase (for MicroLux)
- 7. Seal both cell and supernatant plates and count
- All the Examples of compounds of the present invention described above were tested in the 86Rb+ Efflux Assay described herein and all had potencies of at least 1 µM or lower. Representative examples of data collected for compounds of the present invention using the 86Rb+ Efflux Assay are shown in Table 1 below.
TABLE 1 EXAMPLE NAME 86Rb+ Efflux Assay IC50 (µM) 1 1,4-Bis[2-C4-nitrophenyl)ethyl]piperazine 0.052 35 2-Methoxy-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile trifluoroacetic acid salt 0.089 41 2-Methoxy-4-[2-[4-[2-(4-methyl-1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-vl]ethyl]benzonitrile HCl salt 0.035 59 5,5'-(Piperazine-1,4-diyldiethane-2,1-diyl)bis(4-methyl-2-benzofuran-1(3H)-one) trifluoroacetic acid salt 0.076 67 5,5'-(Piperazine-1,4-diyldiethane-2,1-diyl)bis(2-benzofuran-1(3H)-one 0.089 76 2-Ethoxy-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile bis-HCl salt 0.053 90 4-Fluoro-2-methoxy-3-(2-{4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile bis-HCl salt 0.043 94 4-Methyl-5-(1-{4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}-2-benzofuran-1(3H)-one 0.034 57 2-Methoxy-4-(2-{4-[2-(3-methyl-1-oxo-3,4-dihydro-1H-isochromen-6-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile 0.098 9 2,2-Dimethyl-1,4-bis[2-(4-nitrophenyl)ethyl]piperazine 0.21 10 (1S,4S)-2,5-Bis[2-(4-nitrophenyl)ethyl]-2,5-diazabicyclo[2.2.1]heptane 0.11 26 (6R)-6-{4-[2-(4-Nitrophenyl)ethyl]piperazin-1-yl}-5,6,7,8-tetrahydronaphthalene-2-carbonitrile HCl salt 0.066 43 4-Methyl-5-[2-[4-[2-[6-(tetrazol-1-yl)-3-pyridyl]ethyl]piperazin-1-yl]ethyl]-3H-isobenzofuran-1-one 0.62 56 2-Methoxy-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-2-(trifluoromethyl)piperazin-1-yl}ethyl)benzonitrile trifluoroacetic acid salt 0.27 74 4-(2-{4-[2-(4-Methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)naphthalene-1-carbonitrile bis-HCl salt 0.16 - Cell Culture Conditions- HEK293 cells stably expressing hROMK (hKir1.1) are grown at 37°C in a 10%CO2 humidified incubator in complete growth media: Dulbecco's Modified Eagle Medium supplemented with non-essential amino acids, Penicillin/Streptomycin/Glutamine, G418 and FBS. At >80% confluency, aspirate the media from the flask and rinse with 10 ml Calcium/Magnesium-free PBS. Add 5 ml of 1X trypsin (prepared in Ca/Mg Free PBS) to T-225 flask and return flask to 37°C/CO2 incubator for 2-3 minutes. To dislodge the cell, gently bang the side of the flask with your hand. Triturate the cells completely and then transfer the cells to 25 ml complete media. Centrifuge at 1,500 rpm for 6 min followed by resuspension in complete growth media and determine cell concentration. For typical re-seeding, 4E6 cells/T-225 flask will attain >80% confluency in 4 days. Under ideal growth conditions and appropriate tissue culture practices, this cell line is stable for 40-45 passages.
-
- FluxOR™ Reagent (Component A)
- FluxOR™ Assay Buffer (Component B) - 10X Concentrate
- PowerLoad™ Concentrate (Component C) - 100X Concentrate
- Probenecid (Component D) - Lyophilized sample is kept at -20°C. Water soluble, 100X after solubilization in 1 ml water. Store at 4°C.
- FluxOR™ Chloride-free Buffer (Component E) - 5X Concentrate
- Potassium sulfate (K2SO4) Concentrate (Component F) - 125 mM in water. Store at 4°C.
- Thallium sulfate (Tl2SO4) Concentrate (Component G) - 50 mM in water. Store at 4°C
- DMSO (dimethyl sulfoxide, Component H) - 1 ml (100%)
-
- 1000X FluxOR™ Reagent: Reconstitute a vial of component A in 100 µl DMSO; Mix well; Store 10 µl aliquots at -20°C
- 1X FluxOR™ Assay Bluffer: Dilute Component B 10-fold with water; Adjust pH to 7.4 with Hepes/NaOH; Filter and store at 4°C
- Probenecid/Assay Buffer: 100 ml of 1X FluxOR™ Assay Buffer; 1 ml of reconstituted component D; Store at 4°C
- Loading Buffer (per microplate): 10 µl 1000X FluxOR™ Reagent; 100 µl component C; 10 ml Probenecid/Assay Buffer
- Compound Buffer (per microplate): 20 ml Probenecid/Assay Buffer; 0.3 mM ouabain (10 mM ouabain in water can be stored in amber bottle/aluminum foil at room temperature); Test compound
- 1X FluxOR™Chloride-Free Buffer: Prepare 1X working solution in water. Can be stored at room temperature
- Stimulant Buffer (prepared at 5X final concentration in 1X FluxOR™Chloride-Free Buffer): 7.5 mM Thallium sulfate and 0.75 mM Potassium sulfate (to give a final assay concentration of 3 mM Thallium/ 0.3 mM Potassium). Store at 4°C when not in use. If kept sterile, this solution is good for months.
-
- 1. Seed HEK-hKir1.1 cells (50 µl at 20,000 cells/well) in 384-well PDL coated Microplates
- 2. Allow cells to adhere overnight in humidified 37°C/10%CO2 incubator
- 3. Completely remove cell growth media from microplate and replace with 25 µl loading buffer
- 4. Incubate Microplate at room temperature, protected form light, for 90 min
- 5. Remove loading buffer and replace with 25 µl 1x Assay Buffer ± test compound.
- 6. Incubate microplate at room temperature, protected form light, for 30 min
- 7. At FLIPR-Tetra 384: Add stimulant (Thallium/Potassium) solution to microplate and monitor fluorescence. Excitation = 400 nm, Emission = 460 & 580 nm. Collect data for ∼ 10 min.
- Representative examples of data collected for compounds of the present invention, including Example 95, using the Thallium Flux Assay are shown in Table 2 below.
TABLE 2 EXAMPLE NAME Thallium Flux Assay IC50 (µM) 1 1,4-Bis[2-(4-nitrophenyl)ethyl]piperazine 0.066 95 4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile HCl salt 0.3 58 (3S,3'S)-6,6'-(Piperazine-1,4-diytdiethane-2,1-diyl)bis(3-methyl-3,4-dihydro-1H-isochromen-1-one) 0.24 62 2-(Methylamino)-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile 0.41 38 2-Fluoro-4-[2-[4-[2-(1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile 0.11 94 4-Methyl-5-(1-{4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}-2-benzofuran-1(3H)-one 0.012 64 2-(Cyclopropyloxy)-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile 0.081 86 3-Chloro-2-fluoro-4-(2-{4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile bis-HCl salt 0.017 89 4-Fluoro-2-methoxy-3-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile bis-HCl salt 0.05 - While the invention has been described with reference to certain particular embodiments thereof, numerous alternative embodiments will be apparent to those skilled in the art from the teachings described herein. Recitation or depiction of a specific compound in the claims (i.e., a species) without a specific stereoconfiguration designation, or with such a designation for less than all chiral centers, is intended to encompass the racemate, racemic mixtures, each individual enantiomer, a diastereoisomeric mixture and each individual diastereomer of the compound where such forms are possible due to the presence of one or more asymmetric centers.
Assay Standard- Normally, a control compound is included to support that the assay is giving consistent results compared to previous measurements, although the control is not required to obtain the results for the test compounds. The control can be any compound of Formula I of the present invention, preferably with an IC50 potency of less than 1 µM in this assay. Alternatively, the control could be another compound (outside the scope of Formula I) that has an IC50 potency in this assay of less than 1 µM.
Claims (12)
- A compound having structural Formula I:
Z1 is selected from:
R1 and R2 are each independently selected from -H, -F, -Cl, -Br, -C3-C6cycloalkyl, -OR8, -SR8, -SOR8, -SO2R8, -(CH2)-nOR8 or -C1-6alkyl optionally substituted with 1-3 of -F;
one of R3a and R3b is selected from -CN, -NO2 or tetrazoly, and the other is R3c wherein R3c selected from -H, -F, -Cl, -Br, -CH3, -S-CH3, -NH-CH3, -O-cyclopropyl or -OC1-3alkyl optionally substituted with 1-3 of -F;
one of R4a and R4b is selected from CN, -NO2 or tetrazolyl, and the other is R4c wherein R4c is selected from -H, -F, -Cl, -Br, -CH3, -S-CH3, -NH-CH3, -O-cyclopropyl or -OC1-3alkyl optionally substituted with 1-3 of -F;
Ra , Raa, Rb and Rbb are each independently selected from -H, -F, -Cl, -CH3 optionally substituted with 1 to 3 of -F, or -OCH3 optionally substituted with 1 to 3 of F;
Rc and Rd are each independently selected from -H, -F, -Cl, -C1-6alkyl optionally substituted with 1 to 3 of -F, -C3-6cycloalkyl or -OC1-6alkyl optionally substituted with 1 to 3 of -F;
Re and Rf are each independently selected from -H or -CH3;
X and X1 are each independently selected from -H or -C1-6alkyl,
or X1 is joined together with Z1 and the carbon to which both are attached to form a fused ring system selected from:
or Y1 is joined together with Z2 and the carbon to which both are attached to form a fused ring system selected from
or R5 is joined together with Z1 and the intervening carbons to which each is attached to form a fused ring system selected from: - The compound of claim 1 wherein:X and X1 are each independently selected from -H or -C1-6alkyl;Y and Y1 are each independently selected from -H or -C1-6alkyl,or Y1 is joined together with Z2 and the carbon to which both are attached to form a fused ring system selected from:R5 is selected from -H, -CH3, -C1-6 alkyl or -C(O)OC1-3alkyl; andR6 is selected from -H, -CH3, -C1-6 alkyl or -C(O)OC1-3alkyl,or a pharmaceutically acceptable salt thereof.
- The compound of claim 1 wherein
R7 is -H;
R1 and R2 are independently selected from -H or -CH3;
Ra and Rb are each independently selected from -H, -F, -Cl, -CH3 optionally substituted with 1 to 3 of -F, or -OCH3 optionally substituted with 1 to 3 of -F;
Raa and Rbb are each independently selected from -H or -F
Rc and Rd are each independently selected from -H, -F, -Cl, -CH3 optionally substituted with 1 to 3 of -F, or -OCH3 optionally substituted with 1 to 3 of -F;
R5 is selected from -H or -CH3;
R6 is selected from -H or -CH3; or R6 is joined together with Z2 and the intervening carbons to which each is attached to form a fused ring system;
X, X1 and Y are each -H; and
Y1 is -H, or Y1 is joined together with Z2 and the carbon to which both are attached to form the fused ring system;
or a pharmaceutically acceptable salt thereof. - The compound of claim 1 selected from:1,4-Bis[2-(4-nitrophenyl)ethyl]piperazine;2-Methoxy-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-yl}ethyl)benzonitrile;2-Methoxy-4-[2-[4-[2-(4-methyl-1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl] ethyl]benzonitrile;5,5'-(Piperazine-1,4-diyldiethane-2,1-diyl)bis(4-methyl-2-benzofuran-1(3H)-one);5,5'-(Piperazine-1,4-diyldiethane-2,1-diyl)bis(2-benzofuran-1(3H)-one2-Ethoxy-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;4-Fluoro-2-methoxy-3-(2- {4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;4-Methyl-5-(1-(4-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperazin-1-yl)propan-2-yl)isobenzofuran-1(3H)-one;2-Methoxy-4-(2-{4-[2-(3-methyl-1-oxo-3,4-dihydro-1H-isochromen-6-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;2,2-Dimethyl-1,4-bis[2-(4-nitrophenyl)ethyl]piperazine;(1S,4S)-2,5-Bis[2-(4-nitrophenyl)ethyl]-2,5-diazabicyclo[2.2.1]heptane;(6R)-6-{4-[2-(4-Nitrophenyl)ethyl]piperazin-1-yl}-5,6,7,8-tetrahydronaphthalene-2-carbonitrile;4-Methyl-5-[2-[4-[2-[6-(tetrazol-1-yl)-3-pyridyl]ethyl]piperazin-1-yl]ethyl]-3H-isobenzofuran-1-one;2-Methoxy-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-2-(trifluoromethyl)piperazin-1-yl}ethyl)benzonitrile;4-(2- {4-[2-(4-Methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)naphthalene-1-carbonitrile;4-(2- {4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;(3S,3'S)-6,6'-(Piperazine-1,4-diyldiethane-2,1-diyl)bis(3-methyl-3,4-dihydro-1H-isochromen-1-one);2-(Methylamino)-4-(2- {4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;2-Fluoro-4-[2-[4-[2-(1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]benzonitrile;2-(Cyclopropyloxy)-4-(2- {4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;3-Chloro-2-fluoro-4-(2-{4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile; or4-Fluoro-2-methoxy-3-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;or a pharmaceutically acceptable salt thereof.
- The compound of claim 1 selected from:1,4-Bis[2-(4-nitrophenyl)ethyl]piperazine;4,4'-(Piperazine-1,4-diyldiethane-2,1-diyl)dibenzonitrile;2-Methoxy-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;2-Methoxy-4-[2-[4-[2-(4-methyl-1-oxo-3H-isobenzofuran-5-yl)ethyl]piperazin-1-yl] ethyl]benzonitrile;5,5'-(Piperazine-1,4-diyldiethane-2,1-diyl)bis(4-methyl-2-benzofuran-1(3H)-one);5,5'-(Piperazine-1,4-diyldiethane-2,1-diyl)bis(2-benzofuran-1(3H)-one;2-Ethoxy-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;4-Fluoro-2-methoxy-3-(2- {4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;4-Methyl-5-(1-(4-(2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)piperazin-1-yl)propan-2-yl)isobenzofuran-1(3H)-one;4-(2- {4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile;or a pharmaceutically acceptable salt thereof.
- A pharmaceutical composition comprised of a compound of any previous claim, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
- A compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof for use in inhibiting ROMK.
- A compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof for use in causing diueresis, natriuresis or both.
- A compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof for use in the treatment of hypertension, heart failure or both. sum
- A compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof for use in the treatment or prophylaxis of one or more disorders selected from hepatic cirrhosis, acute and chronic kidney insufficiency, nephrotic syndrome, pulmonary arterial hypertension, cardiovascular disease, diabetes, endothelial dysfunction, diastolic dysfunction, stable and unstable angina pectoris, thromboses, restenosis, myocardial infarction, stroke, cardiac insufficiency, pulmonary hypertonia, atherosclerosis, ascitis, pre-eclampsia, cerebral edema, nephropathy, hypercalcemia, Dent's disease, Meniere's disease or kidney stones.
- A compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof for use in therapy.
- A combination comprising a compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof and one or more additional pharmacologically active agents.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US40718110P | 2010-10-27 | 2010-10-27 | |
US201161473861P | 2011-04-11 | 2011-04-11 | |
PCT/US2011/057346 WO2012058116A1 (en) | 2010-10-27 | 2011-10-21 | Inhibitors of the renal outer medullary potassium channel |
Publications (3)
Publication Number | Publication Date |
---|---|
EP2632465A1 EP2632465A1 (en) | 2013-09-04 |
EP2632465A4 EP2632465A4 (en) | 2014-03-26 |
EP2632465B1 true EP2632465B1 (en) | 2015-12-30 |
Family
ID=45994334
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP11836899.2A Active EP2632465B1 (en) | 2010-10-27 | 2011-10-21 | Inhibitors of the renal outer medullary potassium channel |
Country Status (3)
Country | Link |
---|---|
US (1) | US9073882B2 (en) |
EP (1) | EP2632465B1 (en) |
WO (1) | WO2012058116A1 (en) |
Families Citing this family (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2632464B1 (en) * | 2010-10-29 | 2015-04-29 | Merck Sharp & Dohme Corp. | Inhibitors of the renal outer medullary potassium channel |
CA2844310A1 (en) | 2011-08-19 | 2013-02-28 | Merck Sharp & Dohme Corp. | Inhibitors of the renal outer medullary potassium channel |
TW201317213A (en) | 2011-09-16 | 2013-05-01 | Merck Sharp & Dohme | Inhibitors of the renal outer medullary potassium channel |
US8999991B2 (en) | 2011-10-25 | 2015-04-07 | Merck Sharp & Dohme Corp. | Inhibitors of the renal outer medullary potassium channel |
US8999990B2 (en) | 2011-10-25 | 2015-04-07 | Merck Sharp & Dohme Corp. | Inhibitors of the renal outer medullary potassium channel |
EP2773351B1 (en) | 2011-10-31 | 2017-08-23 | Merck Sharp & Dohme Corp. | Inhibitors of the renal outer medullary potassium channel |
US9108947B2 (en) | 2011-10-31 | 2015-08-18 | Merck Sharp & Dohme Corp. | Inhibitors of the Renal Outer Medullary Potassium channel |
WO2013066714A1 (en) * | 2011-10-31 | 2013-05-10 | Merck Sharp & Dohme Corp. | Inhibitors of the renal outer medullary potassium channel |
EP2790511B1 (en) | 2011-12-16 | 2016-09-14 | Merck Sharp & Dohme Corp. | Inhibitors of the renal outer medullary potassium channel |
WO2014015495A1 (en) * | 2012-07-26 | 2014-01-30 | Merck Sharp & Dohme Corp. | Inhibitors of the renal outer medullary potassium channel |
AR092031A1 (en) * | 2012-07-26 | 2015-03-18 | Merck Sharp & Dohme | INHIBITORS OF THE EXTERNAL RENAL MEDULAR POTASSIUM CHANNEL |
EP2925322B1 (en) | 2012-11-29 | 2018-10-24 | Merck Sharp & Dohme Corp. | Inhibitors of the renal outer medullary potassium channel |
WO2014090700A1 (en) | 2012-12-14 | 2014-06-19 | Basf Se | Malononitrile compounds for controlling animal pests |
WO2014099633A2 (en) | 2012-12-19 | 2014-06-26 | Merck Sharp & Dohme Corp. | Inhibitors of the renal outer medullary potassium channel |
EP2956142B1 (en) | 2013-02-18 | 2017-09-20 | Merck Sharp & Dohme Corp. | Inhibitors of the renal outer medullary potassium channel |
EP2968288B1 (en) | 2013-03-15 | 2018-07-04 | Merck Sharp & Dohme Corp. | Inhibitors of the renal outer medullary potassium channel |
US9751881B2 (en) | 2013-07-31 | 2017-09-05 | Merck Sharp & Dohme Corp. | Inhibitors of the renal outer medullary potassium channel |
EP3083573A4 (en) | 2013-12-18 | 2017-08-02 | Merck Sharp & Dohme Corp. | Inhibitors of the renal outer medullary potassium channel |
US10857121B2 (en) | 2014-04-17 | 2020-12-08 | Merial Inc. | Use of malononitrile compounds for protecting animals from parasites |
WO2016008064A1 (en) | 2014-07-14 | 2016-01-21 | Merck Sharp & Dohme Corp. | Inhibitors of renal outer medullary potassium channel |
AU2015361614B2 (en) | 2014-12-08 | 2019-11-28 | Jiangsu Hengrui Medicine Co., Ltd. | Pyridinecarboxamide derivatives, preparation method therefor and pharmaceutical uses thereof |
CN105693706B (en) * | 2014-12-10 | 2019-11-22 | 江苏恒瑞医药股份有限公司 | Isobenzofuran ketone derivative, preparation method and its application in medicine |
US10513518B2 (en) | 2015-01-29 | 2019-12-24 | Merck Sharp & Dohme Corp. | Inhibitors of the renal outer medullary potassium channel |
WO2016127358A1 (en) | 2015-02-12 | 2016-08-18 | Merck Sharp & Dohme Corp. | Inhibitors of renal outer medullary potassium channel |
ES2962315T3 (en) | 2016-04-20 | 2024-03-18 | Bristol Myers Squibb Co | Substituted bicyclic heterocyclic compounds |
US10723723B2 (en) | 2016-11-03 | 2020-07-28 | Bristol-Myers Squibb Company | Substituted bicycle heterocyclic derivatives useful as ROMK channel inhibitors |
PL3630752T3 (en) | 2017-06-01 | 2021-11-02 | Bristol-Myers Squibb Company | Substituted nitrogen containing compounds |
CN109265352B (en) * | 2018-10-31 | 2021-06-04 | 杭州迈世腾药物科技有限公司 | Preparation method of aryl cyclopropyl ether and derivatives thereof |
CN114539065B (en) * | 2020-11-25 | 2023-07-25 | 帕潘纳(北京)科技有限公司 | Method for preparing 4-nitro-2-trifluoromethyl acetophenone |
Family Cites Families (61)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2988551A (en) | 1954-07-30 | 1961-06-13 | Union Chimique Belge Sa | Piperazine derivatives |
GB949088A (en) | 1961-06-26 | 1964-02-12 | Lepetit Spa | Diazabicyclo-octane derivatives |
US3435002A (en) | 1967-05-15 | 1969-03-25 | Gen Electric | Polyamide acid resins and polyimides therefrom |
GB1575310A (en) | 1976-11-16 | 1980-09-17 | Anphar Sa | Piperidine derivatives |
FR2522325B1 (en) | 1982-02-26 | 1985-08-09 | Delalande Sa | NOVEL ARYLIC DERIVATIVES OF PIPERAZINE, HOMOPIPERAZINE AND N, N'-DIALKYL DIAMINO-1,2 ETHANE, THEIR PREPARATION PROCESS AND THEIR THERAPEUTIC APPLICATION |
NL8202636A (en) | 1982-06-29 | 1984-01-16 | Gist Brocades Nv | PIPERAZINE DERIVATIVES, METHODS FOR PREPARING THE SAME AND PHARMACEUTICAL PREPARATIONS CONTAINING THESE COMPOUNDS. |
DE3471486D1 (en) | 1983-08-15 | 1988-06-30 | Ciba Geigy Ag | PHOTOCURABLE COMPOSITIONS |
US5145885A (en) | 1983-08-15 | 1992-09-08 | Ciba-Geigy Corporation | Photopolymerizable compositions containing aminoaryl ketone photoinitiators |
US4579863A (en) | 1983-12-06 | 1986-04-01 | Warner-Lambert Company | Substituted trans-1,2-diaminocyclohexyl amide compounds |
US4661607A (en) | 1984-09-21 | 1987-04-28 | Chugai Seiyaku Kabushiki Kaisha | Furoxanthone derivatives useful as diuretics |
GB8603120D0 (en) | 1986-02-07 | 1986-03-12 | Pfizer Ltd | Anti-dysrhythmia agents |
US5112824A (en) * | 1989-12-08 | 1992-05-12 | Merck & Co., Inc. | Benzofuran compounds as class III antiarrhythmic agents |
US5215989A (en) | 1989-12-08 | 1993-06-01 | Merck & Co., Inc. | Nitrogen-containing heterocyclic compounds as class III antiarrhythmic agents |
FR2673182A1 (en) | 1991-02-22 | 1992-08-28 | Univ Caen | N,N'-Disubstituted piperazines, process for their preparation and their application in therapeutics |
CA2168264A1 (en) | 1993-07-28 | 1995-02-09 | Yoichi Kawashima | Novel 1, 4-(diphenylalkyl)piperazine derivatives |
US5614526A (en) | 1995-06-09 | 1997-03-25 | Hoffmann-La Roche Inc. | Use of phenoxy-piperzine derivatives |
GB9523250D0 (en) * | 1995-11-14 | 1996-01-17 | Merck Sharp & Dohme | Therapeutic agents |
US6686353B1 (en) | 1996-05-20 | 2004-02-03 | Teijin Intellectual Property Center Limited | Diarylalkyl cyclic diamine derivatives as chemokine receptor antagonists |
DE19637237A1 (en) | 1996-09-13 | 1998-03-19 | Merck Patent Gmbh | Piperazine derivatives |
JPH10203986A (en) | 1997-01-22 | 1998-08-04 | Mitsubishi Chem Corp | Agent for ophthalmic disease |
AU3247700A (en) | 1999-03-03 | 2000-09-21 | Merck & Co., Inc. | Inhibitors of prenyl-protein transferase |
EP1094063A1 (en) | 1999-10-18 | 2001-04-25 | Applied Research Systems ARS Holding N.V. | 9-(Piperazinylalkyl)carbazoles as Bax-modulators |
US6787543B2 (en) | 2000-06-29 | 2004-09-07 | Fujisawa Pharmaceutical Co., Ltd. | Benzhydryl derivatives |
US6352158B1 (en) | 2000-07-06 | 2002-03-05 | Warner Lambert Company | Unit dose blister package with keyhole assisted opening feature |
US6693099B2 (en) | 2000-10-17 | 2004-02-17 | The Procter & Gamble Company | Substituted piperazine compounds optionally containing a quinolyl moiety for treating multidrug resistance |
GB0031088D0 (en) | 2000-12-20 | 2001-01-31 | Smithkline Beecham Plc | Medicaments |
CN1172919C (en) | 2002-06-03 | 2004-10-27 | 上海医药工业研究院 | Alkyl alcohol piperazine derivative and its application in preparing medicine for treating depression |
GB0220214D0 (en) | 2002-08-30 | 2002-10-09 | Novo Pharmaceuticals De Ltd | Compounds and their use |
US20040204404A1 (en) | 2002-09-30 | 2004-10-14 | Robert Zelle | Human N-type calcium channel blockers |
AU2003275632A1 (en) | 2002-10-25 | 2004-05-13 | Mitsubishi Pharma Corporation | N-oxide compounds |
AU2003284402A1 (en) | 2002-11-15 | 2004-06-15 | Yamanouchi Pharmaceutical Co., Ltd. | Antagonist to melanin-concentrating hormone receptor |
ATE361296T1 (en) | 2003-04-03 | 2007-05-15 | Merck Patent Gmbh | PYRAZOLIDINE-1,2-DICARBONONIC ACID 1-((PHENYL)-AMID) 2-((PHENYL)-AMID) DERIVATIVES AS COAGULATION FACTOR XA INHIBITORS FOR THE TREATMENT OF THROMBOSIS |
DE10329457A1 (en) | 2003-04-03 | 2005-01-20 | Merck Patent Gmbh | New 1,2-bis-phenylaminocarbonyl-pyrrolidine derivatives, useful for treating or preventing e.g. thrombosis, myocardial infarct and arteriosclerosis, are inhibitors of coagulation factor Xa |
MXPA05010444A (en) | 2003-04-03 | 2005-11-04 | Merck Patent Gmbh | Pyrrolidino-1, 2-dicarboxy -1-(phenylamide) -2-(4-(3-oxo- morpholino -4-yl)- phenylamide) derivatives and related compounds for use as inhibitors of coagulation factor xa in the treatment of thrombo-embolic diseases. |
JP5015593B2 (en) | 2003-06-18 | 2012-08-29 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング | 1-[(4-Ethynylphenyl)]-2-[(phenyl)]-pyrrolidine-1,2-dicarboxamide derivatives as inhibitors of coagulation factors Xa and VIIa for the treatment of thrombosis |
MXPA06001636A (en) | 2003-08-13 | 2006-04-28 | Amgen Inc | Melanin concentrating hormone receptor antagonist. |
CN1897950A (en) | 2003-10-14 | 2007-01-17 | 惠氏公司 | Fused-aryl and heteroaryl derivatives and methods of their use |
GB0325956D0 (en) | 2003-11-06 | 2003-12-10 | Addex Pharmaceuticals Sa | Novel compounds |
AR051094A1 (en) | 2004-09-20 | 2006-12-20 | Xenon Pharmaceuticals Inc | HETEROCICLIC DERIVATIVES AND THEIR USE AS INHIBITORS OF ESTEAROIL-COA DESATURASA |
DE102004045796A1 (en) | 2004-09-22 | 2006-03-23 | Merck Patent Gmbh | Medicaments containing carbonyl compounds and their use |
DE102004047254A1 (en) | 2004-09-29 | 2006-04-13 | Merck Patent Gmbh | carbonyl |
WO2006098342A1 (en) | 2005-03-16 | 2006-09-21 | Astellas Pharma Inc. | Piperazinyl compounds |
GB0510139D0 (en) | 2005-05-18 | 2005-06-22 | Addex Pharmaceuticals Sa | Novel compounds B1 |
US7754724B2 (en) | 2005-06-30 | 2010-07-13 | Dow Agrosciences Llc | N-substituted piperazines |
WO2007009462A2 (en) | 2005-07-15 | 2007-01-25 | Region Hovedstaden V/Glostrup Hospital | Treatment of migraine and headaches |
BRPI0616574A2 (en) | 2005-09-27 | 2009-11-24 | Shionogi & Co | sulfonamide derivative having pgd2 receptor antagonistic activity |
AU2006331882A1 (en) | 2005-12-21 | 2007-07-05 | Schering Corporation | Phenoxypiperidines and analogs thereof useful as histamine H3 antagonists |
WO2008008517A2 (en) | 2006-07-14 | 2008-01-17 | Merck & Co., Inc. | Bridged diazepan orexin receptor antagonists |
WO2008147864A2 (en) | 2007-05-22 | 2008-12-04 | Xenon Pharmaceuticals Inc. | Methods of using piperazine compounds in treating sodium channel-mediated diseases or conditions |
EP2303850A4 (en) | 2008-06-13 | 2012-10-31 | Bionomics Ltd | Novel potassium channel blockers and uses thereof |
US8673920B2 (en) | 2009-05-06 | 2014-03-18 | Merck Sharp & Dohme Corp. | Inhibitors of the renal outer medullary potassium channel |
EP2632464B1 (en) | 2010-10-29 | 2015-04-29 | Merck Sharp & Dohme Corp. | Inhibitors of the renal outer medullary potassium channel |
CA2844310A1 (en) | 2011-08-19 | 2013-02-28 | Merck Sharp & Dohme Corp. | Inhibitors of the renal outer medullary potassium channel |
TW201317213A (en) | 2011-09-16 | 2013-05-01 | Merck Sharp & Dohme | Inhibitors of the renal outer medullary potassium channel |
US8999991B2 (en) | 2011-10-25 | 2015-04-07 | Merck Sharp & Dohme Corp. | Inhibitors of the renal outer medullary potassium channel |
US8999990B2 (en) | 2011-10-25 | 2015-04-07 | Merck Sharp & Dohme Corp. | Inhibitors of the renal outer medullary potassium channel |
US9108947B2 (en) | 2011-10-31 | 2015-08-18 | Merck Sharp & Dohme Corp. | Inhibitors of the Renal Outer Medullary Potassium channel |
EP2773351B1 (en) | 2011-10-31 | 2017-08-23 | Merck Sharp & Dohme Corp. | Inhibitors of the renal outer medullary potassium channel |
WO2013066714A1 (en) | 2011-10-31 | 2013-05-10 | Merck Sharp & Dohme Corp. | Inhibitors of the renal outer medullary potassium channel |
EP2790511B1 (en) | 2011-12-16 | 2016-09-14 | Merck Sharp & Dohme Corp. | Inhibitors of the renal outer medullary potassium channel |
AR092031A1 (en) | 2012-07-26 | 2015-03-18 | Merck Sharp & Dohme | INHIBITORS OF THE EXTERNAL RENAL MEDULAR POTASSIUM CHANNEL |
-
2011
- 2011-10-21 EP EP11836899.2A patent/EP2632465B1/en active Active
- 2011-10-21 US US13/881,008 patent/US9073882B2/en active Active
- 2011-10-21 WO PCT/US2011/057346 patent/WO2012058116A1/en active Application Filing
Non-Patent Citations (1)
Title |
---|
G. BHAVE ET AL: "Development of a Selective Small-Molecule Inhibitor of Kir1.1, the Renal Outer Medullary Potassium Channel", MOLECULAR PHARMACOLOGY, vol. 79, no. 1, January 2011 (2011-01-01), pages 42 - 50, XP055101486, ISSN: 0026-895X, DOI: 10.1124/mol.110.066928 * |
Also Published As
Publication number | Publication date |
---|---|
EP2632465A1 (en) | 2013-09-04 |
WO2012058116A1 (en) | 2012-05-03 |
US9073882B2 (en) | 2015-07-07 |
EP2632465A4 (en) | 2014-03-26 |
US20130225561A1 (en) | 2013-08-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP2632465B1 (en) | Inhibitors of the renal outer medullary potassium channel | |
EP2773199B1 (en) | Inhibitors of the renal outer medullary potassium channel | |
EP2771005B1 (en) | Inhibitors of the renal outer medullary potassium channel | |
EP2771004B1 (en) | Inhibitors of the renal outer medullary potassium channel | |
EP2427444B1 (en) | Inhibitors of the renal outer medullary potassium channel | |
EP2773206B1 (en) | Inhibitors of the renal outer medullary potassium channel | |
EP2773351B1 (en) | Inhibitors of the renal outer medullary potassium channel | |
EP2755656B1 (en) | Inhibitors of the renal outer medullary potassium channel | |
EP2632464B1 (en) | Inhibitors of the renal outer medullary potassium channel | |
EP2925322B1 (en) | Inhibitors of the renal outer medullary potassium channel | |
EP2934533B1 (en) | Inhibitors of the renal outer medullary potassium channel | |
US9604998B2 (en) | Inhibitors of the renal outer medullary potassium channel | |
AU2015357290B2 (en) | 1-[2-(aminomethyl)benzyl]-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-ones as inhibitors of myeloperoxidase |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20130527 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
DAX | Request for extension of the european patent (deleted) | ||
A4 | Supplementary search report drawn up and despatched |
Effective date: 20140225 |
|
RIC1 | Information provided on ipc code assigned before grant |
Ipc: C07D 413/12 20060101ALI20140219BHEP Ipc: C07D 271/04 20060101ALI20140219BHEP Ipc: C07D 295/073 20060101ALI20140219BHEP Ipc: C07D 471/08 20060101ALI20140219BHEP Ipc: C07D 405/12 20060101ALI20140219BHEP Ipc: C07D 487/08 20060101ALI20140219BHEP Ipc: C07D 213/76 20060101ALI20140219BHEP Ipc: A61K 31/497 20060101AFI20140219BHEP Ipc: C07D 241/04 20060101ALI20140219BHEP |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R079 Ref document number: 602011022353 Country of ref document: DE Free format text: PREVIOUS MAIN CLASS: A61K0031497000 Ipc: C07D0213610000 |
|
GRAJ | Information related to disapproval of communication of intention to grant by the applicant or resumption of examination proceedings by the epo deleted |
Free format text: ORIGINAL CODE: EPIDOSDIGR1 |
|
GRAP | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOSNIGR1 |
|
RIC1 | Information provided on ipc code assigned before grant |
Ipc: C07D 295/155 20060101ALI20150115BHEP Ipc: C07D 271/12 20060101ALI20150115BHEP Ipc: C07D 213/61 20060101AFI20150115BHEP Ipc: C07D 307/88 20060101ALI20150115BHEP Ipc: C07D 295/15 20060101ALI20150115BHEP Ipc: C07D 295/13 20060101ALI20150115BHEP Ipc: C07D 309/30 20060101ALI20150115BHEP |
|
INTG | Intention to grant announced |
Effective date: 20150130 |
|
GRAS | Grant fee paid |
Free format text: ORIGINAL CODE: EPIDOSNIGR3 |
|
GRAP | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOSNIGR1 |
|
INTG | Intention to grant announced |
Effective date: 20150625 |
|
GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE PATENT HAS BEEN GRANTED |
|
AK | Designated contracting states |
Kind code of ref document: B1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: FG4D |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: EP |
|
REG | Reference to a national code |
Ref country code: AT Ref legal event code: REF Ref document number: 767407 Country of ref document: AT Kind code of ref document: T Effective date: 20160115 |
|
REG | Reference to a national code |
Ref country code: IE Ref legal event code: FG4D |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R096 Ref document number: 602011022353 Country of ref document: DE |
|
REG | Reference to a national code |
Ref country code: LT Ref legal event code: MG4D |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: HR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20151230 Ref country code: NO Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20160330 Ref country code: LT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20151230 |
|
REG | Reference to a national code |
Ref country code: NL Ref legal event code: MP Effective date: 20151230 |
|
REG | Reference to a national code |
Ref country code: AT Ref legal event code: MK05 Ref document number: 767407 Country of ref document: AT Kind code of ref document: T Effective date: 20151230 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: SE Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20151230 Ref country code: LV Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20151230 Ref country code: GR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20160331 Ref country code: RS Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20151230 Ref country code: FI Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20151230 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: NL Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20151230 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: IT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20151230 Ref country code: ES Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20151230 Ref country code: CZ Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20151230 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: AT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20151230 Ref country code: RO Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20151230 Ref country code: PL Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20151230 Ref country code: SM Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20151230 Ref country code: IS Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20160430 Ref country code: PT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20160502 Ref country code: EE Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20151230 Ref country code: SK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20151230 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: PLFP Year of fee payment: 6 |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R097 Ref document number: 602011022353 Country of ref document: DE |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: DK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20151230 |
|
PLBE | No opposition filed within time limit |
Free format text: ORIGINAL CODE: 0009261 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT |
|
26N | No opposition filed |
Effective date: 20161003 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: BE Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20151230 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: SI Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20151230 |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PL |
|
REG | Reference to a national code |
Ref country code: IE Ref legal event code: MM4A |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LI Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20161031 Ref country code: CH Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20161031 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LU Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20161021 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: PLFP Year of fee payment: 7 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: IE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20161021 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: HU Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO Effective date: 20111021 Ref country code: CY Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20151230 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: MK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20151230 Ref country code: MT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20161031 Ref country code: MC Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20151230 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: BG Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20151230 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: PLFP Year of fee payment: 8 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: AL Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20151230 Ref country code: TR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20151230 |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R081 Ref document number: 602011022353 Country of ref document: DE Owner name: MERCK SHARP & DOHME LLC, RAHWAY, US Free format text: FORMER OWNER: MERCK SHARP & DOHME CORP., RAHWAY, N.J., US |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: 732E Free format text: REGISTERED BETWEEN 20221013 AND 20221019 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: GB Payment date: 20230914 Year of fee payment: 13 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: FR Payment date: 20230914 Year of fee payment: 13 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: DE Payment date: 20230915 Year of fee payment: 13 |